Analgesic compounds, their preparation, and pharmaceutical compositions containing them

ABSTRACT

Analgesic compounds of the formula (I); ##STR1## in which, R 1  and R 2  each represents hydrogen or C 1  -C 6  alkyl, or R 1  and R 2  together with the nitrogen atom to which they are attached form a heterocycle; E represents oxygen or an imino group optionally substituted with C 1  -C 6  alkyl or aralkyl; ring A is an aryl or heteroaryl ring, optionally substituted; R 3  is hydrogen or C 1  -C 6  alkyl and R 4  is hydrogen or R 3  and R 4  together represent a group of formula (IV): 
     
         --(CR.sup.a R.sup.a).sub.m --C(═Y)--                   (IV) 
    
     wherein R a  and R a  is C 1  -C 6  alkyl or hydrogen, up to a maximum of 3 alkyl groups, m is 1, 2, or 3, and Y is two hydrogens or oxygen; provided that when E represents a methylene group, then R 3  is a C 1  -C 6  alkyl group or R 3  and R 4  together represent a group of the formula (IV).

This application is a continuation of application Ser. No. 08/140,602filed Oct. 21, 1993 abandoned, which is a division of application Ser.No. 07/943,386 filed Sep. 10, 1992 (now U.S. Pat. No. 5,270,327), whichis a continuation of application Ser. No. 07/627,736 filed Dec. 14, 1990(abandoned), which is a division of application Ser. No. 07/397,105filed Aug. 22, 1989 (now U.S. Pat. No. 5,021,413).

BACKGROUND OF THE INVENTION

The present invention relates to carboxylic acid amide derivatives andpharmaceutically acceptable acid addition salts thereof, being compoundswhich have useful analgesic and other pharmaceutical activity, andfurther relates to the preparation of such compounds.

In general, analgesic drugs acting on κ-receptors do not show the sideeffects such as dependence, drug tolerance and respiratory inhibitionshown by the morphine-like analgesic drugs acting on μ-receptors.Furthermore, analgesic drugs acting on κ-receptors do not show crossresistance to morphine. Accordingly, the analgesic drugs acting onκ-receptors are of considerable interest, because an agent which doesnot evince respiratory inhibition is useful for management ofpost-operative patients suffering from pain. Moreover, an agent withoutcross resistance is significant in clinical uses, for example, forpatients suffering from cancer pain where tolerance to morphine andother antagonistic analgesic agents has occurred.

By way of example, European Patent Specification 232612 published on 19Aug. 1987 discloses azacyclic compounds which exhibit κ-receptoragonism. The compounds are without the behavioural effects of morphineand morphine analogs, and are thus of potential therapeutic utility asanalgesics. A small class of compounds within the generality of EuropeanPatent Specification 232612 and said to have improved properties aredisclosed in European Patent Specification 260041 published on 16 Mar.1988.

OBJECTS OF THE PRESENT INVENTION

The objects of the present invention include compounds which havepharmacological activity and in particular are useful as analgesicagents. Further objects comprise pharmaceutical compositions withanalgesic or other pharmacological activity, as well as methods for therelief of pain using the compounds and processes for the preparation ofsuch compounds.

SUMMARY OF THE PRESENT INVENTION

The present invention provides compounds of the general formula (I);##STR2## in which, R¹ and R² are the same or different and eachrepresents a hydrogen atom or a C₁ -C₆ alkyl group, or R¹ and R²together with the nitrogen atom to which they are attached form aheterocyclic ring;

E represents a methylene group, a sulfur atom, an oxygen atom or animino group optionally substituted with a C₁ -C₆ alkyl group or anaralkyl group;

the ring A represents an aryl ring; a heteroaryl ring; an aryl ringsubstituted with at least one substituent selected from Group (i); or aheteroaryl ring substituted with at least one substituent selected fromGroup (i);

said Group (i) comprising halogen atoms, C₁ -C₆ alkyl groups,halogenated C₁ -C₆ alkyl groups, C₁ -C₆ alkoxy groups, halogenated C₁-C₆ alkoxy groups, C₁ -C₆ alkylthio groups, aryl groups, acyl groups,nitro groups, and hydroxy groups;

R³ represents a hydrogen atom or a C₁ -C₆ alkyl group and R⁴ representsa hydrogen atom, or R³ and R⁴ together represent a group of formula(IV);

    --(CR.sup.a R.sup.b).sub.m --C(═Y)--                   (IV)

(wherein each R^(a) R^(b) represents hydrogen or a C₁ -C₃ alkyl group,provided that there are not more than three alkyl groups in the group offormula (IV), m represents 1, 2, or 3, and Y represents two hydrogenatoms or an oxygen atom);

provided that when E represents a methylene group, then R³ is a C₁ -C₆alkyl group or R³ and R⁴ together represent a group of the formula

and pharmaceutically acceptable salts thereof.

Compounds wherein E represents a methylene group, and R³ and R⁴ bothrepresent hydrogen atoms are excluded in view of the disclosure inEuropean Patent Specification 232612, mentioned above.

The present invention thus embraces compounds of general formula (I) andsalts thereof, wherein R³ is a C₁ -C₆ alkyl group and R⁴ is a hydrogenatom, or R³ and R⁴ together represent said group of formula (IV); andfurther embraces compounds of formula (I) wherein E is selected from thegroup consisting of a sulfur atom, an oxygen atom, an imino group, andimino groups substituted with a substituent selected from the groupconsisting of C₁ -C₆ alkyl groups and aralkyl groups; and R³ and R⁴ bothrepresent hydrogen atoms.

PREFERRED EMBODIMENT OF THE PRESENT INVENTION

Preferred embodiments include those compounds wherein R¹ and R² are thesame or different and each is a C₁ -C₆ alkyl group, or R¹ and R²together with the nitrogen atom to which they are attached form a 5- or6-membered heterocyclic ring;

E is selected from the group consisting of a methylene group, a sulfuratom and an imino group;

ring A is selected from the group consisting of aryl rings; heteroarylrings; aryl rings substituted with at least one substituent of Group(ii); and heteroaryl rings substituted with at least one substituent ofGroup (ii);

said Group (ii) being a subset of Group (i) and comprising halogenatoms, halogenated C₁ -C₆ alkyl groups, and C₁ -C₆ alkyl groups;

R³ and R⁴ both represent hydrogen atoms, or R³ and R⁴ together representa group of formula (IV);

    --(CR.sup.a R.sup.b).sub.m --C(═Y)--                   (IV)

(wherein each R^(a) and R^(b) represents hydrogen or a C₁ -C₃ alkylgroup, provided that there is not more than one alkyl group in the groupof formula (IV), m represents 1, or 2, and Y represents two hydrogenatoms or an oxygen atom);

and pharmaceutically acceptable salts thereof.

More preferred embodiments include those compounds wherein R¹ and R² arethe same or different and each is a C₁ -C₃ alkyl group, or R¹ and R²together with the nitrogen atom to which they are attached form apyrrolidine ring or a piperidine ring;

E is selected from the group consisting of a methylene group and asulfur atom;

ring A is selected from the group consisting of aryl rings; heteroarylrings; and aryl rings substituted with at least one substituent selectedfrom the group consisting of halogen atoms, halogenated C₁ -C₃ alkylgroups, and C₁ -C₃ alkyl groups;

R³ and R⁴ both represent hydrogen atoms, or R³ and R⁴ together representa group of formula (IV);

    --(CR.sup.a R.sup.b).sub.m --C (═Y)--                  (IV)

(wherein each R^(a) R^(b) and represents a hydrogen atom, m represents1, or 2, and Y represents two hydrogen atoms or an oxygen atom);

and pharmaceutically acceptable salts thereof.

Most preferred embodiments include those compounds wherein R¹ and R²together with the nitrogen atom to which they are attached form apyrrolidine ring or a piperidine ring;

E is selected from the group consisting of a methylene group and asulfur atom;

ring A is selected from the group consisting of aryl rings and arylrings substituted with at least one substituent selected from the groupconsisting of halogen atoms and C₁ -C₃ alkyl groups;

R³ and R⁴ together represent a group of formula (IV);

    --(CR.sup.a R.sup.b).sub.m --C(═Y)--                   (IV)

(wherein each R^(a) and R^(b) represents hydrogen atom, m represents 1,or 2, and Y represents two hydrogen atoms or an oxygen atom);

and pharmaceutically acceptable salts thereof.

Further embodiments include;

compounds wherein R¹ and R² together with the nitrogen atom to whichthey are attached form a pyrrolidine ring or a piperidine ring;

E is selected from the group consisting of a methylene group and asulfur atom;

ring A is an aryl ring substituted with at least one substituentselected from the group consisting of halogen atoms and C₁ -C₃ alkylgroups;

R³ and R⁴ together represent a group of formula (IV);

    --(CR.sup.a R.sup.b).sub.m --C(═Y)--                   (IV)

(wherein each R^(a) and R^(b) represents a hydrogen atom, m represents 1or 2, and Y represents two hydrogen atoms or an oxygen atom);

compounds wherein R¹ and R² both represent C₁ -C₃ alkyl groups;

E is selected from the group consisting of a methylene group and asulfur atom;

ring A is selected from the group consisting of aryl rings; aryl ringssubstituted with at least one substituent selected from the groupcomprising halogen atoms and C₁ -C₃ alkyl groups;

R³ and R⁴ together represent a group of formula (IV);

    --(CR.sup.a R.sup.b).sub.m --C(═Y)--                   (IV)

(wherein each R^(a) and R^(b) represents a hydrogen atom, m represents 1or 2, and Y represents two hydrogen atoms or an oxygen atom);

compounds wherein R¹ and R² both represent C₁ -C₃ alkyl groups;

E is selected from the group consisting of a methylene group and asulfur atom;

ring A is an aryl ring substituted with at least one substituentselected from the group consisting of halogen atoms and C₁ -C₃ alkylgroups;

R³ and R⁴ together represent a group of formula (IV);

    --(CR.sup.a R.sup.b).sub.m --C(═Y)--                   (IV)

(wherein each R^(a) and R^(b) represents a hydrogen atom, m represents 1or 2, and Y represents two hydrogen atoms or an oxygen atom)

compounds wherein R¹ and R² together with the nitrogen atom to whichthey are attached form a pyrrolidine ring or a piperidine ring;

compounds wherein E is selected from the group consisting of a methylenegroup and a sulfur atom;

compounds wherein ring A is selected from the group consisting of arylrings and aryl rings substituted with at least one substituent selectedfrom the group consisting of halogen atoms and C₁ -C₃ alkyl groups; and

compounds wherein R³ and R⁴ together represent a group of formula (IV);

    --(CR.sup.a R.sup.b).sub.m --C(═Y)--                   (IV)

(wherein each R^(a) and R^(b) represents a hydrogen atom, m represents1, or 2, and Y represents two hydrogen atoms or an oxygen atom);

and pharmaceutically acceptable salts thereof.

In the general formula (I), the groups R¹ and R² are the same ordifferent and each represents a hydrogen atom, or a straight or branchedchain C₁ -C₆ alkyl group preferably having from 1 to 3 carbon atoms.Examples of suitable alkyl groups include a methyl, ethyl, propyl,isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl,2-methylbutyl, t-pentyl, neopentyl, hexyl, 4-methylpentyl,3-methylpentyl, 2-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,3-dimethylbutyl, or1,3-dimethylbutyl group. Of these, a methyl, ethyl, propyl, or isopropylgroup is preferred.

Alternatively, R¹ and R² together with the nitrogen atom to which theyare attached form a heterocyclic ring, preferably a saturatedheterocyclic ring, and more preferably a 5- or 6-membered N-heterocycleoptionally having a further heteroatom which may be oxygen, nitrogen orsulfur. Examples of suitable heterocyclic radicals represented by suchrings include an imidazolidinyl, hexahydropyridazinyl,hexahydropyrimidinyl, piperazinyl, hexamethyleneimino,1,2-diazacycloheptyl, 1,3-diazacycloheptyl, homopiperazinyl, pyrrolyl,azepinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, acridyl,tetrahydroacridyl, pyrrolidinyl, piperidino, tetrahydroquinolyl,tetrahydroisoquinolyl, isoindolyl, indolinyl or 6-azabicyclo3.2.1!oct-6-yl group. The heterocyclic ring may be substituted with astraight or branched chain C₁ -C₆ alkyl group, preferably an alkyl grouphaving 1 to 3 carbon atoms. For example, a 6-azabicyclo 3.2.1!oct-6-ylring may be 1,3,3-trimethyl substituted, and a piperazine ring may beN-substituted for instance with a straight or branched chain C₁ -C₆alkyl group, preferably an alkyl group having 1 to 3 carbon atoms, suchas a methyl, ethyl, propyl or isopropyl group. Preferred heterocyclicrings which may be formed by R¹ and R² comprise a pyrrolidine,piperidine, N-methylpiperazine, morpholine, hexamethyleneimino orthiazolidine ring.

Particularly preferred examples for the group formed by R¹ and R²together with the nitrogen to which they are attached include monoalkyl-and dialkyl-substituted amino groups in which the or each alkyl groupcontains from 1 to 6, preferably from 1 to 3, carbon atoms such as amethylamino, ethylamino, propylamino, isopropylamino, butylamino,isobutylamino, dimethylamino, diethylamino, dipropylamino,diisopropylamino, pentylamino or hexylamino group, of which amethylamino, dimethylamino, ethylamino, propylamino, or isopropylaminogroup is preferred. The particularly preferred examples for the groupformed by R¹ and R² together with the nitrogen to which they areattached further include a heterocyclic radical such as a1-pyrrolidinyl, 1-piperidyl (that is, piperidino),1-(4-methyl)piperazinyl, 1-hexamethyleneiminyl, 3-thiazolidinyl, or4-morpholinyl (that is, morpholino) group.

The symbol E represents a methylene group, a sulfur atom, an oxygen atomor an imino group. The imino group can be substituted with a C₁ -C₆alkyl group or with an aralkyl group having 1 to 4 carbon atoms in thealkyl part and 6 or 10 carbon atoms in the aryl part. Examples of suchsubstitutent groups for an imino group include a benzyl, phenethyl,1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl,4-phenylbutyl, 1-naphthylmethyl or 2-naphthylmethyl groups, morepreferably a C₇ -C₉ aralkyl group such as a benzyl group.

The ring A is preferably an aromatic ring such as an aryl ring, forinstance a benzene or naphthalene ring, or a 5- to 7-membered heteroarylring containing 1 to 3 oxygen heteroatoms, nitrogen heteroatoms and/orsulfur heteroatoms, optionally condensed with a further ring. Heteroarylexamples for the ring A include a furan, thiophene, pyrazole, imidazole,oxazole, isoxazole, thiazole, isothiazole, triazole, thiadiazole,pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, oracridine ring. Preferably the ring A is a benzene ring or a 5- or6-membered heteroaryl ring containing 1 heteroatom, such as a thiophene,furan or pyridine ring.

The ring A may be substituted by one or more substituents, preferably 1to 3 substituents, and typically 1 or 2 substituents, the substituentsbeing of the Group (i). Such substituents may be halogen atoms such as afluorine, chlorine, bromine and/or iodine atom; straight or branchedchain C₁ -C₆ alkyl groups, typically those mentioned for R¹ or R², andpreferably straight or branched chain alkyl groups having 1 to 3 carbonatoms such as a methyl, ethyl, n-propyl or isopropyl group; aryl groups,preferably a C₆ or C₁₀ aryl group, that is a phenyl or naphthyl group;acyl groups, typically carboxylic acyl groups, preferably aliphatic acylgroups containing from 1 to 6, more preferably 1 to 4, carbon atoms suchas a formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaloyl or hexanoyl group, of which a formyl, acetyl,propionyl, butyryl or isobutyryl group is especially preferred; straightor branched chain C₁ -C₆ alkoxy groups, preferably having 1 to 3 carbonatoms, such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, pentyloxy, isopentyloxy, t-pentyloxy or hexyloxy group; nitrogroups; halogenated C₁ -C₆ alkyl or alkoxy groups, preferably C₁ -C₃alkyl or alkoxy groups such as a fluoromethyl, difluoromethyl,trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 3-fluoropropyl, 4-fluorobutyl, 5-fluoropentyl,6-fluorohexyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl,4,4-difluorobutyl, 4,4,4-trifluorobutyl, bromomethyl, dibromomethyl,trichloromethyl, 1-chloroethyl, 2-bromoethyl, 2,2-dibromoethyl,2,2,2-trichloroethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy,2,2,2-trifluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy,5-fluoropentyloxy, 6-fluorohexyloxy, 3,3-difluoropropoxy,3,3,3-trifluoropropoxy, 4,4-difluorobutoxy or 4,4,4-trifluorobutoxygroup, of which a fluoromethyl, difluoromethyl, trifluoromethyl,1-fluoroethyl, 1,2-fluoroethyl, 2,2-difluoroethyl or2,2,2-trifluoroethyl group is especially preferred; hydroxy groups; orstraight or branched chain C₁ -C₆ alkylthio groups, preferably straightor branched chain alkylthio groups having 1 to 3 carbon atoms, such as amethylthio, ethylthio, n-propylthio, isopropylthio, butylthio,isobutylthio, s-butylthio, t-butylthio, pentylthio, isopentylthio,2-methylbutylthio, t-pentylthio, neo-pentylthio, hexylthio,4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio,3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio,1,2-dimethylbutylthio, 2,3-dimethylbutylthio, or 1,3-dimethylbutylthiogroup.

Typical examples for the ring A include an aryl ring which is notsubstituted, such as, for example, a benzene or naphthalene ring; anaryl ring which is substituted with an alkyl group such as, for example,a 4-methylbenzene, 2-methylbenzene, 3-methylbenzene, 4-ethylbenzene,4-butylbenzene, 2-propylbenzene, 3-hexylbenzene, 2,3-dimethylbenzene,3,4-dimethylbenzene, 2,5-dimethylbenzene, 2,6-dimethylbenzene,2,4-dimethylbenzene, 2,3-diethylbenzene, 3,4-dipropylbenzene,2,5-dibutylbenzene, 2,6-dipentylbenzene, 2,4-dihexylbenzene,2,3,6-trimethylbenzene, 2,3,4-trimethylbenzene, 3,4,5-trimethylbenzene,2,5,6-trimethylbenzene, 2,4,6-trimethylbenzene, 2,3,6-triethylbenzene,2,3,4-tripropylbenzene, 3,4,5-tributylbenzene, 2,5,6-tripentylbenzene,2,4,6-trihexylbenzene, 1-methyl-2-naphthalene, 2-methyl-1-naphthalene,3-methyl-1-naphthalene, 2-ethyl-1-naphthalene, 1-butyl-2-naphthalene,2-propyl-1-naphthalene, 3-hexyl-1-naphthalene,2,3-dimethyl-1-naphthalene, 3,8-dimethyl-1-naphthalene,4,8-dimethyl-1-naphthalene, 5,6-dimethyl-1-naphthalene,2,4-dimethyl-1-naphthalene, 2,3-diethyl-1-naphthalene,3,4-dipropyl-1-naphthalene, 4,5-dibutyl-1-naphthalene,5,6-dipentyl-1-naphthalene, 2,4-dihexyl-1-naphthalene,2,3,6-trimethyl-1-naphthalene, 2,3,4-trimethyl-1-naphthalene,3,4,5-trimethyl-1-naphthalene, 4,5,6-trimethyl-1-naphthalene,2,4,8-trimethyl-1-naphthalene, 2,3,6-trimethyl-1-naphthalene,2,3,4-tripropyl-1-naphthalene, 3,4,8-tributyl-1-naphthalene,4,5,6-tripentyl-1-naphthalene or 2,4,6-trihexyl-1-naphthalene ring; anaryl ring which is substituted with a halogen atom such as, for example,a 4-fluorobenzene, 2-fluorobenzene, 3-fluorobenzene, 4-bromobenzene,2-iodobenzene, 3-chlorobenzene, 4-chlorobenzene, 3,5-difluorobenzene,2,5-difluorobenzene, 2,5-diiodobenzene, 2,6-difluorobenzene,2,4-difluorobenzene, 2,3-dichlorobenzene, 3,4-dichlorobenzene,2,5-dichlorobenzene, 2,6-dichlorobenzene, 2,4-dibromobenzene,2,3,6-trifluorobenzene, 2,3,4-trifluorobenzene, 3,4,5-trifluorobenzene,2,5,6-trifluorobenzene, 2,4,6-trifluorobenzene, 2,3,6-trichlorobenzene,2,3,4-trichlorobenzene, 3,4,5-tribromobenzene, 2,5,6-tribromobenzene,2,4,6-tribromobenzene, 1-fluoro-2-naphthalene, 2-fluoro-1-naphthalene,3-fluoro-1-naphthalene, 2-chloro-1-naphthalene, 1-chloro-2-naphthalene,2-bromo-1-naphthalene, 3-bromo-1-naphthalene,2,3-difluoro-1-naphthalene, 3,8-difluoro-1-naphthalene,4,8-difluoro-1-naphthalene, 5,6-difluoro-1-naphthalene,2,4-difluoro-1-naphthalene, 2,3-dichloro-1-naphthalene,3,4-dichloro-1-naphthalene, 4,5-dichloro-1-naphthalene,5,6-dibromo-1-naphthalene, 2,4-dibromo-1-naphthalene,2,3,6-trifluoro-1-naphthalene, 2,3,4-trifluoro-1-naphthalene,3,4,5-trifluoro-1-naphthalene, 4,5,6-trifluoro-1-naphthalene,2,4,8-trifluoro-1-naphthalene, 2,3,6-trichloro-1-naphthalene,2,3,4-trichloro-1-naphthalene 3,4,8-tribromo-1-naphthalene,4,5,6-tribromo-1-naphthalene or 2,4,6-tribromo-1-naphthalene ring; anaryl ring which is substituted with a lower alkoxy group such as, forexample, a 4-methoxybenzene, 2-methoxybenzene, 3-methoxybenzene,4-ethoxybenzene-4-propoxybenzene, 2-butoxybenzene, 3-ethoxybenzene,3,5-dimethoxybenzene, 2,5-dimethoxybenzene, 2,5-dipropoxybenzene,2,6-dimethoxybenzene, 2,4-dimethoxybenzene, 2,3-diethoxybenzene,3,4-diethoxybenzene, 2,5-diethoxybenzene, 2,6-diethoxybenzene,2,4-dipropoxybenzene, 2,3,6-trimethoxybenzene, 2,3,4-trimethoxybenzene,3,4,5-trimethoxybenzene, 2,5,6-methoxybenzene, 2,4,6-trimethoxybenzene,2,3,6-triethoxybenzene, 2,3,4-triethoxybenzene, 3,4,5-tripropoxybenzene,2,5,6-tripropoxybenzene, 2,4,6-tripropoxybenzene,1-methoxy-2-naphthalene, 2-methoxy-1-naphthalene,3-methoxy-1-naphthalene, 2-ethoxy-1-naphthalene, 1-ethoxy-2-naphthalene,2-propoxy-1-naphthalene, 3-propoxy-1-naphthalene,2,3-dimethoxy-1-naphthalene, 3,8-dimethoxy-1-naphthalene,4,8-dimethoxy-1-naphthalene, 5,6-dimethoxy-1-naphthalene,2,4-dimethoxy-1-naphthalene, 2,3-dimethoxy-1-naphthalene,3,4-diethoxy-1-naphthalene, 4,5-diethoxy-1-naphthalene,5,6-dipropoxy-1-naphthalene, 2,4-dipropoxy-1-naphthalene,2,3,6-trimethoxy-1-naphthalene, 2,3,4-trimethoxy-1-naphthalene,3,4,5-trimethoxy-1-naphthalene, 4,5,6-trimethoxy-1-naphthalene,2,4,8-trimethoxy-1-naphthalene, 2,3,6-triethoxy-1-naphthalene,2,3,4-triethoxy-1-naphthalene, 3,4,8-tripropoxy-1-naphthalene,4,5,6-tripropoxy-1-naphthalene or 2,4,6-tripropoxy-1-naphthalene ring;an heteroaryl ring which is unsubstituted, such as, for example, athiophene or furan ring; an heteroaryl ring which is substituted with analkyl group such as, for example, a 4-methylthiophene,2-methylthiophene, 3-methylthiophene, 4-ethylthiophene,4-butylthiophene, 2-propylthiophene, 3-hexylthiophene,2,3-dimethylthiophene, 3,4-dimethylthiophene, 2,5-dimethylthiophene,2,4-dimethylthiophene, 2,3-diethylthiophene, 3,4-dipropylthiophene,2,5-dibutylthiophene, 2,4-dihexylthiophene, 2,3,4-trimethylthiophene,3,4,5-trimethylthiophene, 2,3,4-tripropylthiophene,3,4,5-tributylthiophene; an heteroaryl ring which is substituted with ahalogen atom such as, for example, a 4-fluorothiophene,2-fluorothiophene, 3-fluorothiophene, 4-bromothiophene, 2-iodothiophene,3-chlorothiophene, 3,5-difluorothiophene, 2,5-difluorothiophene,2,5-diiodothiophene, 2,4-difluorothiophene, 2,3-dichlorothiophene,3,4-dichlorothiophene, 2,5-dichlorothiophene, 2,4-dibromothiopheneo2,3,4-trifluorothiophene, 3,4,5-trifluorothiophene,2,3,4-trichlorothiophene, or 3,4,5-tribromothiophene ring; an heteroarylring which is substituted with a lower alkoxy group such as, forexample, a 4-methoxythiophene, 2-methoxythiophene, 3-methoxythiophene,4-ethoxythiophene, 4-propoxythiophene, 2-butoxythiophene,3-ethoxythiophene, 3,5-dimethoxythiophene, 2,5-dimethoxythiophene,2,5-dipropoxythiophene, 2,4-dimethoxythiophene, 2,3-diethoxythiophene,3,4-diethoxythiophene, 2,5-diethoxythiophene, 2,4-dipropoxythiophene,2,3,4-trimethoxythiophene, 3,4,5-trimethoxythiophene,2,3,4-triethoxythiophene, or 3,4,5-tripropoxythiophene ring; an arylring which is substituted with an alkylthio group such as, for example,a 4-methylthiobenzene, 2-methylthiobenzene, 3-methylthiobenzene,4-ethylthiobenzene, 4-butylthiobenzene, 2-propylthiobenzene, or3-hexylthiobenzene ring; an heteroaryl ring which is substituted with analkylthio group such as, for example, a 4-methylthiothiophene,2-methylthiothiophene, 3-methylthiothiophene, 4-ethylthiothiophene, or4-butylthiothiophene ring; an aryl ring which is substituted with ahydroxy group such as, for example, a 4-hydroxybenzene,2-hydroxybenzene, or 3-hydroxybenzene ring; an heteroaryl ring which issubstituted with a hydroxy group such as, for example, a4-hydroxythiophene, 2-hydroxythiophene, 3-hydroxythiophene ring; an arylring which is substituted with a nitro group such as, for example, a4-nitrobenzene, 2-nitrobenzene, or 3-nitrobenzene ring; or an heteroarylring which is substituted with a nitro group such as, for example, a4-nitrothiophene, 2-nitrothiophene, 3-nitrothiophene ring.

Preferred examples for the ring A include an aryl or heteroaryl ringwhich is not substituted, or a benzene or thiophene ring substituted byone or more halogen atoms such as a fluorine or chlorine atom; by one ormore C₁ -C₃ alkyl groups such as a methyl or ethyl group; by a C₁ -C₃alkoxy group such as a methoxy or ethoxy; by a hydroxy group; by a nitrogroup; or by a C₁ -C₃ alkylthio group such as a methylthio group.

R³ is a hydrogen atom or a C₁ -C₆ alkyl group and R⁴ is a hydrogen atom.In this case, it is preferred that R³ is a hydrogen atom or a C₁ -C₃alkyl group and R⁴ is a hydrogen atom, and more preferred that both R³and R⁴ represent hydrogen atoms. R³ and R⁴ can alternatively togetherrepresent a group of formula (IV);

    --(CR.sup.a R.sup.b).sub.m --C(═Y)--                   (IV)

(wherein each R^(a) and R^(b) represents hydrogen or a C₁ -C₃ alkylgroup, provided that there are not more than three alkyl groups in thegroup of formula (IV), m represents 1, 2, or 3, and Y represents twohydrogen atoms or an oxygen atom). In this case, the compounds offormula (I) are then of the general formula (Ia); ##STR3## In theformulae (Ia) and (IV), both R^(a) and R^(b) preferably representhydrogen atoms, and m is preferably 1 or 2.

The present invention further embraces pharmaceutically acceptablenon-toxic salts of the compounds of general formula (I). Examples ofsuitable salts include acid addition salts with an inorganic acid forinstance a hydrohalogenated acid such as hydrofluoric acid, hydrochloricacid, hydrobromic acid or hydroiodic acid, or nitric acid, perchloricacid, sulfuric acid, phosphoric acid or the like acid; and acid additionsalts with an organic acid for instance a lower alkyl sulfonic acid suchas methanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonicacid, an aryl sulfonic acid such as benzenesulfonic acid orp-toluenesulfonic acid, an amino acid such as glutamic acid or asparticacid, or an organic carboxylic acid such as fumaric acid, succinic acid,citric acid, tartaric acid, oxalic acid, mandelic acid, maleic acid orthe like acid.

The compounds of general formula (I) exist in more than onestereoisomeric form, and this invention embraces individual isomers aswell as mixtures. It will often be the case that one stereoisomer ismore active than another, as may be determined by routine testing.

Preferred isomers of this invention include those compounds and saltswherein

the group E is a methylene group and the configuration at the carbonhaving the substituent --CH₂ NR¹ R² is the (S) configuration;

the group E is a sulphur atom and the configuration at the carbon havingthe substituent --CH₂ NR¹ R² is the (R) configuration;

the group E is an oxygen atom and the configuration at the carbon havingthe substituent --CH₂ NR¹ R² is the (R) configuration; or

the group E is an optionally substituted imino group and theconfiguration at the carbon having the substituent --CH₂ NR¹ R² has thechirality corresponding to the (R) configuration for the case where E isan imino group and the substituent is --CH₂ NH₂. In this last respect,the nomenclature for the configuration at the carbon having thesubstituent --CH₂ NR¹ R² for compounds with the preferred chirality willbe (R) or (S), depending on the nature of the imino substituent, thegroup R¹ and the group R².

Furthermore, the compounds of this invention may exist as solvates,particularly hydrates, and this invention extends to such solvates.

Compounds of the general formula (I) in accordance with the presentinvention are exemplified by the following compounds, by their salts,especially the hydrochloride or methanesulfonate salts, and by theirindividual diastereoisomers and their individual optical isomers.

1. 1-(indan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidine

2. 1-(3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidine

3.1-(5-chloro-3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidine

4.1-(5-methyl-3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidine

5. 1-(5-nitro-3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidine

6.1-(5-methoxy-3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidine

7.1-(6-chloro-3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidine

8.1-(6-methoxy-3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidine

9.1-(5,6-dichloro-3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidine10.1-(4,5-dichloro-3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidine

11.1-(6-hydroxy-3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidine

12.4-(5-methyl-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)morpholine

13.4-(6,7-dichloro-1,2,3,4-tetrahydronaphthoyl)-3-(piperidinomethyl)thiomorpholine

14. 1-(5,6-dichloroindan-1-carbonyl)-2-(piperidinomethyl)piperidine

15. 1-(3-oxoindan-1-carbonyl)-2-(piperidinomethyl)piperidine

16.1-(5,6-dichloro-3-oxoindan-1-carbonyl)-2-(piperidinomethyl)piperidine

17.2-(pyrrolidin-1-ylmethyl)-1-(1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)piperidine

18.1-(6,7-dichloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)-2-(pyrrolidin-1-ylmethyl)piperidine

19. 4,5-dihydro-6-oxo-4-2-(pyrrolidin-1-ylmethyl)piperidine-1-carbonyl!-6H-cyclopentab!thiophene

20. 4,5-dihydro-6-oxo-4-2-(pyrrolidin-1-ylmethyl)piperidine-1-carbonyl!-6H-cyclopenta b!furan

21. 2-chloro-4,5-dihydro-6-oxo-4-2-(pyrrolidin-1-ylmethyl)piperidine-1-carbonyl!-6H-cyclopentab!thiophene

22.1-(5,6-dichloro-3-oxoindan-1-carbonyl)-2-(4-methylpiperazin-1-ylmethyl)piperidine

23. 4-2-(3,4-dichlorophenyl)propionyl!-3-(pyrrolidin-1-ylmethyl)thiomorpholine

24. 4-2-(3,4-dichlorophenyl)propionyl!-3-(pyrrolidin-1-ylmethyl)morpholine

25. 4,5-dihydro-6-oxo-4-3-(pyrrolidin-1-ylmethyl)thiomorpholine-4-carbonyl!-6H-cyclopentab!thiophene

26. 4,5-dihydro-4-3-(pyrrolidin-1-ylmethyl)thiomorpholine-4-carbonyl!-6H-cyclopentab!thiophene

27. 4,5-dihydro-6-oxo-4-3-(pyrrolidin-1-ylmethyl)thiomorpholine-4-carbonyl!-6H-cyclopentab!furan

28. 4,5,6,7-tetrahydro-7-oxo-4-3-(pyrrolidin-1-ylmethyl)thiomorpholine-4-carbonyl!benzo b!thiophene

29.4-(2,2-dimethyl-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

30. 4-(3,4-dichlorophenylacetyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

31. 4-(4-chlorophenyl acetyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

32. 4-(4-methylphenyl acetyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

33. 4-(4-methoxyphenylacetyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

34. 4-(4-methylthiophenylacetyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

35. 4-(4-nitrophenylacetyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

36. 4-(3,4-dichlorophenylacetyl)-3-(pyrrolidin-1-ylmethyl)morpholine

37. 4-(4-chlorophenylacetyl)-3-(pyrrolidin-1-ylmethyl)morpholine

38. 4-(4-methylphenylacetyl)-3-(pyrrolidin-1-y1methyl)morpholine

39. 4-(4-methoxyphenylacetyl)-3-(pyrrolidin-1-ylmethyl)morpholine

40. 4-(4-methylthiophenylacetyl)-3-(pyrrolidin-1-ylmethyl)morpholine

41. 4-(4-nitrophenylacetyl)-3-(pyrrolidin-1-ylmethyl)morpholine

42.1-(3,4-dichlorophenylacetyl)-4-methyl2-(pyrrolidin-1-ylmethyl)piperazine

43. 1-(4-chlorophenylacetyl)-4-methyl2-(pyrrolidin-1-ylmethyl)piperazine

44.4-methyl-1-(4-methylphenylacetyl)-2-(pyrrolidin-1-ylmethyl)piperazine

45.1-(4-methoxyphenylacetyl)-4-methyl-2-(pyrrolidin-1-ylmethyl)piperazine

46.4-methyl-1-(4-methylthiophenylacetyl)-2-(pyrrolidin-1-ylmethyl)piperazine

47. 4-methyl-1-(4-nitrophenylacetyl)-2-(pyrrolidin-1-ylmethyl)piperazine

48. 4-(4-biphenylacetyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

49. 4-(3,4-dichlorophenylacetyl)-3-(piperidinomethyl)thiomorpholine

50. 4-(3,4-dichlorophenylacetyl)-3-(morpholinomethyl)thiomorpholine

51. 3-(pyrrolidin-1-ylmethyl)-4-(2-thienylacetyl)thiomorpholine

52. 4-(1-naphthylacetyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

53. 4-(3-pyridylacetyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

54. 4-(4-biphenylacetyl)-3-(pyrrolidin-1-ylmethyl)morpholine

55. 4-(3,4-dichlorophenylacetyl)-3-(piperidinomethyl)morpholine

56. 4-(3,4-dichlorophenylacetyl)-3-(morpholinomethyl)morpholine

57. 3-(pyrrolidin-1-ylmethyl)-4-(2-thienylacetyl)morpholine

58. 4-(1-naphthylacetyl)-3-(pyrrolidin-1-ylmethyl)morpholine

59. 4-(3-pyridylacetyl)-3-(pyrrolidin-1-ylmethyl)morpholine

60. 4-methyl-2-(pyrrolidin-1-ylmethyl)-1-(2-thienylacetyl)piperazine

61. 4-methyl -1-(1-naphthylacetyl)-2-(pyrrolidin-1-ylmethyl)piperazine

62. 4-methyl-1-(3-pyridylacetyl)-2-(pyrrolidin-1-ylmethyl)piperazine

63. 4-(3,4-dichlorophenylacetyl)-3-(dimethylaminomethyl)thiomorpholine

64. 4-(3,4-dichlorophenylacetyl)-3-(dimethylaminomethyl)morpholine

65. 4-(3,4-difluorophenylacetyl)-3-(pyrrolidin-1-ylmethyl)morpholine

66.4-(3,4-dichlorophenylacetyl)-3-(4-methylpiperazin-1-ylmethyl)morpholine

67. 4-(indan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

68. 4-(3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

69. 4-(5-chloroindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

70.4-(5-chloro-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

71.4-(5-isopropylindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

72. 4-(5-methylindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

73.4-(5-methyl-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

74.4-(5-methoxyindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

75.4-(5-methoxy-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

76.4-(5-isopropyl-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

77.4-(7-chloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

78.4-(7-chloro-1,3,4-tetrahydro-1-naphthoyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

79.4-(6,7-dichloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

80.4-(6,7-dichloro-1,2,3,4-tetrahydro-1-naphthoyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

81.4-(7-chloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)-3-(morpholinomethyl)thiomorpholine

82.4-(7-chloro-1,2,3,4-tetrahydro-1-naphthoyl)-3-(morpholinomethyl)thiomorpholine

83.4-(6,7-dichloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)-3-(morpholinomethyl)thiomorpholine

84.4-(6,7-dichloro-1,2,3,4-tetrahydro-1-naphthoyl)-3-(morpholinomethyl)thiomorpholine

85.4-(6,7-difluoro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

86.4-(6,7-difluoro-1,2,3,4-tetrahydro-1-naphthoyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

87.3-(pyrrolidin-1-ylmethyl)-4-(1,2,3,4-tetrahydro-7-methyl-4-oxo-1-naphthoyl)thiomorpholine

88.3-(pyrrolidin-1-ylmethyl)-4-(1,2,3,4-tetrahydro-7-methyl-1-naphthoyl)thiomorpholine

89.3-(pyrrolidin-1-ylmethyl)-4-(1,2,3,4-tetrahydro-7-isopropyl-4-oxo-1-naphthoyl)thiomorpholine

90.3-(pyrrolidin-1-ylmethyl)-4-(1,2,3,4-tetrahydro-7-isopropyl-1-naphthoyl)thiomorpholine

91.4-(1,2,3,4-tetrahydro-7-methyl-4-oxo-1-naphthoyl)-3-(morpholinomethyl)thiomorpholine

92.3-(morpholinomethyl)-4-(1,2,3,4-tetrahydro-7-methyl-1-naphthoyl)thiomorpholine

93.3-(morpholinomethyl)-4-(1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)thiomorpholine

94.3-(morpholinomethyl)-4-(1,2,3,4-tetrahydro-1-naphthoyl)thiomorpholine

95. 4-(5,6-dichloroindan-1-carbonyl)-3-(morpholinomethyl)thiomorpholine

96.4-(5,6-dichloroindan-1-carbonyl)-3-(4-methylpiperazin-1-ylmethyl)thiomorpholine

97.4-(5,6-dichloro-3-oxoindan-1-carbonyl)-3-(morpholinomethyl)thiomorpholine

98.4-(5,6-dichloro-3-oxoindan-1-carbonyl)-4-methylpiperazin-1-ylmethyl)thiomorpholine

99. 4-(indan-1-carbonyl)-3-(piperidinomethyl)thiomorpholine

100. 4-(3-oxoindan-1-carbonyl)-3-(piperidino methyl)thiomorpholine

101. 4-(5-chloroindan-1-carbonyl)-3-(piperidinomethyl)thiomorpholine

102.4-(5-chloro-3-oxoindan-1-carbonyl)-3-(piperidinomethyl)thiomorpholine

103. 4-(6-chloroindan-1-carbonyl)-3-(piperidinomethyl)thiomorpholine

104. 4-(5-methylindan-1-carbonyl)-3-(piperidinomethyl)thiomorpholine

105.4-(5-methyl-3-oxoindan-1-carbonyl)-3-(piperidinomethyl)thiomorpholine

106. 4-(5-isopropylindan-1-carbonyl)-3-(piperidinomethyl)thiomorpholine

107.4-(5-isopropyl-3-oxoindan-1-carbonyl)-3-(piperidinomethyl)thiomorpholine

108.4-(6-chloro-3-oxoindan-1-carbonyl)-3-(piperidinomethyl)thiomorpholine

109.4-(6-chloroindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

110.4-(6-chloro-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

111.4-(6-methylindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

112.4-(6-methyl-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

113.4-(5,6-dichloroindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

114.4-(6-methoxyindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

115.4-(6-methoxy-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

116.4-(6-isopropylindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

117.4-(6-isopropyl-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

118.4-(5,6-dichloro-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

119.3-(piperidinomethyl)-4-(1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)thiomorpholine

120.3-(piperidinomethyl)-4-(1,2,3,4-tetrahydro-1-naphthoyl)thiomorpholine

121.4-(6-chloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)-3-(piperidinomethyl)thiomorpholine

122.4-(6-chloro-1,2,3,4-tetrahydro-1-naphthoyl)-3-(piperidinomethyl)thiomorpholine

123.3-(piperidinomethyl)-4-(1,2,3,4-tetrahydro-6-methyl-4-oxo-1-naphthoyl)thiomorpholine

124.3-(piperidinomethyl)-4-(1,2,3,4-tetrahydro-6-methyl-1-naphthoyl)thiomorpholine

125. 4-(3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)morpholine

126.4-(5-chloro-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)morpholine

127.4-(5,6-dichloro-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)morpholine

128.3-(pyrrolidin-1-ylmethyl)-4-(1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)morpholine

129.3-(pyrrolidin-1-ylmethyl)-4-(1,2,3,4-tetrahydro-1-naphthoyl)morpholine

130.4-(6,7-dichloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)-3-(pyrrolidin-1-ylmethyl)morpholine

131.4-(6,7-dichloro-1,2,3,4-tetrahydro-1-naphthoyl)-3-(pyrrolidin-1-ylmethyl)morpholine

132.4-(5-chloro-3-oxoindan-1-carbonyl)-3-(dimethylaminomethyl)morpholine

133.4-methyl-1-(3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperazine

134. 1-(indan-1-carbonyl)-4-methyl-2-(pyrrolidin-1-ylmethyl)piperazine

135.3-(pyrrolidin-1-ylmethyl)-4-(1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)thiomorpholine

136.3-(pyrrolidin-1-ylmethyl)-4-(1,2,3,4-tetrahydro-1-naphthoyl)thiomorpholine

137.4-(6-chloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

138.4-(6-chloro-1,2,3,4-tetrahydro-1-naphthoyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

139.3-(pyrrolidin-1-ylmethyl)-4-(1,2,3,4-tetrahydro-6-methyl-4-oxo-1-naphthoyl)thiomorpholine

140.3-(pyrrolidin-1-ylmethyl)-4-(1,2,3,4-tetrahydro-6-methyl-1-naphthoyl)thiomorpholine

141.3-(pyrrolidin-1-ylmethyl)-4-(1,2,3,4-tetrahydro-6-isopropyl-4-oxo-1-naphthoyl)thiomorpholine

140.3-(pyrrolidin-1-ylmethyl)-4-(1,2,3,4-tetrahydro-6-isopropyl-1-naphthoyl)thiomorpholine

141.4-(5,6-difluoroindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

142.4-(5,6-difluoro-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

145.4-(5,6-dimethylindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

146.4-(5,6-dimethyl-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

147. 4-(6-methylindan-1-carbonyl)-3-(piperidinomethyl)thiomorpholine

148.4-(6-methyl-3-oxoindan-1-carbonyl)-3-(piperidinomethyl)thiomorpholine

149. 4-(6-isopropylindan-1-carbonyl)-3-(piperidinomethyl)thiomorpholine

150.4-(6-isopropyl-3-oxoindan-1-carbonyl)-3-(piperidinomethyl)thiomorpholine

151. 4-(5,6-dichloroindan-1-carbonyl)-3-(piperidinomethyl)thiomorpholine

152. 4-(5,6-dimethylindan-1-carbonyl)-3-(piperidinomethyl)thiomorpholine

153.4-(5,6-dimethyl-3-oxoindan-1-carbonyl)-3-(piperidinomethyl)thiomorpholine

154. 4-(5,6-difluoroindan-1-carbonyl)-3-(piperidinomethyl)thiomorpholine

155.4-(5,6-difluoro-3-oxoindan-1-carbonyl)-3-(piperidinomethyl)thiomorpholine

156.4-(5,6-dichloro-3-oxoindan-1-carbonyl)-3-(piperidinomethyl)thiomorpholine

157.1-(5-chloro-3-oxoindan-1-carbonyl)-4-methyl-2-(pyrrolidin-1-ylmethyl)piperazine

158.1-(5-chloroindan-1-carbonyl)-4-methyl-2-(pyrrolidin-1-ylmethyl)piperazine

159. 4-(5-chloroindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)morpholine

160.4-methyl-2-(pyrrolidin-1-ylmethyl)-1-(1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)piperazine

161.4-methyl-2-(pyrrolidin-1-ylmethyl)-1-(1,2,3,4-tetrahydro-1-naphthoyl)piperazine

162.5,6-dichloro-3-oxoindan-1-carbonyl)-4-methyl-2-(pyrrolidin-1-ylmethyl)piperazine

163.1-(5,6-dichloroindan-1-carbonyl)-4-methyl-2-(pyrrolidin-1-ylmethyl)piperazine

164.1-(6-chloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)-4-methyl-2-(pyrrolidin-1-ylmethyl)piperazine

165. 1-(1,2,3,4-tetrahydro -6-chloro-1-naphthoyl)-4-methyl-2-(pyrrolidin-1-ylmethyl)piperazine

166.1-(5-methyl-3-oxoindan-1-carbonyl)-4-methyl-2-(pyrrolidin-1-ylmethyl)piperazine

167.4-(5-methyl-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)piperazine

168.1-(6,7-dichloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)-4-methyl-2-(pyrrolidin-1-ylmethyl)piperazine

169.1-(6,7-dichloro-1,2,3,4-tetrahydro-1-naphthoyl)-4-methyl-2-(pyrrolidin-1-ylmethyl)piperazine

170.4-(5,6-dichloro-3-oxoindan-1-carbonyl)-3-(morpholinomethyl)morpholine

171.4-(6,7-dichloro-4-oxo-1,2,3,4-tetrahydro-1-naphthoyl)-3-(piperidinomethyl)thiomorpholine

172.1-(5-methylthio-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

173.1-(5,6-dichloroindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidine

174.1-(5,6-dichloro-3-oxoindan-1-carbonyl)-2-(morpholinomethyl)piperidine

175. 4-2-(3,4-dichlorophenyl)propionyl!-3-(pyrrolidin-1-ylmethyl)thiomorpholine

176.4-(5-trifluoromethyl-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

Preferred compounds within this list include Compound Numbers 1, 2, 4,9, 10, 13, 14, 16, 17, 19, 20, 23, 24, 25, 26, 28, 30, 32, 36, 38, 42,44, 49, 50, 51, 55, 56, 57, 60, 63, 64, 65, 68, 69, 70, 71, 72, 73, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 91, 95, 96, 97, 98, 99, 102, 104,105, 110, 111, 112, 113, 118, 119, 120, 121, 123, 125, 126, 127, 130,131, 132, 135, 136, 137, 138, 139, 140, 143, 144, 147, 148, 151, 154,155, 156, 160, 162, 164, 168, 170, 171, 172, 173 and 175 and theirsalts, especially their hydrochlorides, and their isomeric forms.

More preferred compounds within this list include Compound Numbers 9,10, 13, 14, 17, 23, 30, 32, 49, 63, 72, 73, 79, 80, 102, 105, 110,113,118, 123, 127, 130, 137, 139, 144, 147, 148,151, 156, 162, and 171,and their salts, especially their hydrochlorides, and their isomericforms.

Most preferred compounds within this list include Compound Numbers 9,13, 30, 72, 73, 79, 80, 113, 118, 151, 156, and 171, and their salts,especially their hydrochlorides, and their isomeric forms.

The novel carboxylic acid amide derivatives of this invention, includingthe acid addition salts, exhibit useful pharmacological effects, such asanti-inflammatory and analgesic activity.

The pharmacological activity of compounds of this invention was examinedaccording to recognised procedures.

p-Phenylquinone-induced writhing in mice

Testing was performed essentially according to the procedure of Siegmundet al. reported in Proceedings of Society for Experimental Biology &Medicine 95, 729 (1957).

Male ddY mice (Japan SLC) each weighing about 20 g were divided intogroups each including from 5 to 10 mice, and were fasted for 16 hoursfrom the day before the test. A compound to be tested was dissolved inphysiological saline, and injected subcutaneously. After 15 minutes, 0.1ml/mouse of 0.03% p-phenylquinone was injected intraperitoneally. Fiveminutes later, the frequency of writhing reactions in the mouse wascounted for the following 10 minutes. For the control mice, onlyphysiological saline solution was injected. Mice in which the frequencyof writhing reactions was decreased to a half or less of the meanfrequency of writhing reactions in the control mice were regarded asanalgesic-effective mice. The ratio, analgesic-effective animals/allanimals, was obtained for every dosage, and then ED₅₀ values (50%effective dose) were calculated according to the probit method. For sometest compounds the test was modified to determine the writhing effect ata dose of 320 μg/kg.

Affinity to receptors

A raw preparation from brain membrane was made according to the methodof Pasuternak et al. Molecular Pharmacology 11, 340 (1975)!. The wholebrains were taken from male Hartley guinea pigs each weighing from 400to 700 g (Japan SLC) and the cerebella were removed. One part of thewhole brain sample was homogenized in 30 parts of ice-cooled 50 mM Trisbuffer solution (pH 7.4) by use of a Polytron homogenizer, and then,centrifuged for 15 minutes at 49,000 ×g. The precipitated pellet wassuspended in the same kind of buffer. The suspension was incubated for30 minutes at 37° C., and centrifuged for 15 minutes at 49,000 ×g. Onepart of the precipitate was suspended in 30 parts of the buffersolution, and preserved at -80° C. Before use, the suspension wasmelted, homogenized using a Dounce-type homogenizer, and diluted to afinal protein concentration of 0.5 mg/ml.

Binding to κ-receptors was tested essentially according to the methodreported in Archives of Pharmacology 319, 197 (1982) by Magnan et al.Taking 0.6 nM of tritium-labelled ethylketocyclazocine as a labelledligand, binding to the brain membranous preparation was examined byaddition of 100 nM of DAGO (D-Ala², MePhe⁴, Gly-ol⁵ enkephalin) and 10nM of DADLE ( D-Ala², D-Leu⁵ !-enkephalin) to saturate the μ- andδ-receptors. The membranous preparation, labelled ligand, cold ligandand compound to be tested were incubated in 1 ml of Tris buffer at 25°C. for 45 minutes. Then, the mixture was mixed with 5 ml of ice-cooledbuffer solution, filtered through Watmann GF/B filter paper underreduced pressure, and washed twice. The filter paper was placed in anemulsion scintillator (ACS-II) and allowed to stand overnight, and thenthe radioactivity was measured by a liquid scintillation counter. Theaffinity of test compound to the receptor was assessed as theconcentration required to inhibit binding of the labelled ligand by 50%(IC₅₀, nM).

Binding to μ-receptors was tested according to the procedure of Magnanet al. mentioned above. By using 1 nM of tritium-labelled DAGO as alabelled ligand, the test was carried out in a similar manner to thatmentioned in the experiment for testing binding to κ-receptors. Theaffinity of test compound was assessed as an IC₅₀.

The results of the tests are summarized in the following Table, andindicate that compounds of general formula (I), and acid addition salts,are useful as analgesic agents.

                  TABLE    ______________________________________           Analgesic effect           Phenylquinone-  Binding to           induced writhing                           opioid receptors    Example  ED.sub.50             (IC.sub.50, nM)    compound μg/kg s.c.                        320 μg/kg                                   k      μ    ______________________________________    1        6.20                  1.75   1068    2-E.sub.1             1.73                  0.90   232    4-D.sub.1             3.43                  1.40   531    2-E.sub.2             320                   258    10000    4-D.sub.2             270                   366    10000    17                  5/5        1.1    --    36       3.4                   2.4    1135    41-D.sub.1             1.3                   0.67   698.2    U-50488E 490        2/5        9.92   636    Morphine 480        2/5        552    5.1    HCl    ______________________________________

Compound U-50488E is trans-3,4-dichloro-N-methyl-N-2-(1-pyrrolidinyl)cyclohexyl!benzeneacetamide, see J. Pharmacol. Exp.Ther. (1983) 224, 7

For the administration route of the compounds of this invention, theremay be mentioned injection; the oral route using tablets, capsules,granules, powders or syrups; the perintestinal route usingsuppositories; or the parenteral route using ointments, creams orpatches. Though variable depending on the symptoms, age, body weight andother factors, the usual daily dose for an adult person for the typicaladministration routes is 0.005 mg to 10 mg given by injection, 0.01 to10 mg given by patches, or 0.1 mg to 100 mg given by oral route. Thedaily dosage may be given once or divided into several doses.

The novel compounds of the present invention of general formula (I) canbe synthesized by conventional processes such as those employed foramide synthesis, using starting materials which are known or which maybe prepared by analogy with the preparation of known compounds.

Typically, an acid of general formula (II); ##STR4## (wherein R³, R⁴ andring A are as defined) is reacted optionally in the form of a derivativewith an amine of general formula (III); ##STR5## (wherein R¹, R² and Eare as defined).

For example, the acid of the general formula (II) may be employed in thereaction with the amine of the general formula (III) in the form of aderivative which is an acyl halide such as acyl chloride, acyl bromide,or acyl iodide. Such a reaction can be carried out in the presence of abase in an inert solvent. Preferred bases include an organic amine suchas triethylamine or DBU; or an inorganic base such as sodium carbonate,potassium carbonate, sodium hydroxide or potassium hydroxide. Asappropriate depending mainly on the choice of base, the solvent can bean organic solvent or an aqueous solvent. Preferred organic solventsinclude a halogenated hydrocarbon such as methylene chloride,chloroform, carbon tetrachloride or 1,2-dichloroethane; or an ether suchas diethyl ether, tetrahydrofuran or 1,4-dioxane. Preferred aqueoussolvents include water or aqueous organic solvents. For this reaction inthe case of using an organic or inorganic base in an organic solvent,the temperature is usually from -30° C. to the reflux temperature of thesolvent, more typically from -10° C. to room temperature. On the otherhand, for this reaction in the case of using an organic or inorganicbase in an aqueous solvent, the temperature is usually from -5° to 0° C.Though variable depending on the reaction temperature and the like, thereaction usually takes from 30 minutes to 3 hours.

In another example of synthesis of the present compounds, the acid ofthe general formula (II) may be employed in the reaction with the amineof the general formula (III) in the form of a derivative which is amixed acid anhydride. Such an anhydride can readily be obtained byreacting the acid for instance with a haloformate of general formulaHal--COOR⁵ (where R⁵ represents a C₁ -C₃ alkyl group such as a methyl orethyl group, and Hal represents a halogen atom such as a chlorine orbromine atom), in the presence of organic base in an inert solvent togive a mixed acid anhydride. For the solvent, a halogenated hydrocarbonsuch as methylene chloride, 1,2-dichloroethane, carbon tetrachloride orchloroform, an amide such as dimethylformamide, or an ether such asdiethyl ether, tetrahydrofuran or 1,4-dioxane is preferred. For theorganic base, a tertiary amine such as triethylamine, N-methylmorpholineor an organic amine such as pyridine is preferred. The reaction ispreferably carried out at from -20° C. to the reflux temperature of thesolvent employed, and usually requires from 30 minutes to 12 hours. Theresulting acid anhydride can then be allowed to react with an aminecompound of the general formula (III). Usually this reaction is carriedout without isolation of the anhydride from the solvent containingorganic base, but more generally the reaction is carried out usingconditions similar to those mentioned above for the reaction of an acylchloride with the amine (III).

In a further example of amide formation, the reaction using a condensingreagent; for example, the Mukaiyama reaction can be employed. Thisreaction is generally performed in the presence of a condensing reagentsuch as triphenylphosphine and 2,2'-pyridine disulfide (for a Mukaiyamareaction), or 1,3-dicyclohexylcarbodiimide (DCC), in an inert solvent.The solvent is typically a polar solvent such as an ether, for exampletetrahydrofuran, a nitrile, for example acetonitrile, or an amide, forexample dimethylformamide. The reaction is normally carried out at from-20° C. to 100° C. Though variable depending on the reactiontemperature, the reaction usually requires 30 minutes to 24 hours.

Variations in the process employed for production of the compounds ofgeneral formula (I) can be adopted. For instance, the acid of thegeneral formula (II) may be employed in the reaction with the amine ofthe general formula (III) in the form of a derivative which is anappropriately unsaturated acid. Such an unsaturated acid may be reactedwith the amine to form an unsaturated amide, which is then reduced togive a compound of formula (I). This method can be generally employed toproduce compounds of formula (I) where R³ and R⁴ represent the group offormula (IV) and thus form a ring fused to ring A. In this instance, thestarting acid can have a double bond in the ring fused to the ring A,which double bond may be reduced in conventional manner after amideformation. In particular, for the preparation of 3-oxoindan-1-carbonylamides, the starting acid may be a 3-oxo-1-indene-1-carboxylic acidwhich is reacted optionally as a reactive derivative with an amine ofgeneral formula (III) and then reduced to convert the indene ring to anindan ring.

After completion of the amide formation, the desired compound of thegeneral formula (I) can be obtained from the reaction mixture byconventional means. The compound can be purified, for example, bychromatography or by preparing an acid addition salt such as ahydrochloride.

In general, the compounds of the general formula (I) can, if desired, beconverted into a pharmaceutically acceptable acid addition salt bytreatment with an inorganic acid such as hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid or phosphoric acid, or with anorganic acid such as oxalic acid, fumaric acid, maleic acid, mandelicacid, citric acid, tartaric acid, benzenesulfonic acid,p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid.

The compounds of the general formula (I) exist as diastereoisomers andoptical isomers, due to the presence of asymmetric carbon atoms in themolecule. If desired, one or more of the isomers of compound (I) can beseparated from a mixture of the isomers by a conventional isolationmethod, or the optical isomers of compound (I) can be obtained by amideformation using an optically resolved starting material of generalformula (II) and/or (III).

EXAMPLES OF THE INVENTION

The present invention is illustrated by the following non-limitingExamples, which include a Pharmaceutical Example and a PreparativeExample. Some compounds prepared in the Examples are diastereoisomersfor which the absolute configuration is not known. For such compounds,prefixes R* or S* are employed, indicating the compound in question is aracemic mixture. Thus, (1S*, 2S*) means a 1:1 mixture of (1R, 2R) and(1S, 2S) and is the same as (1R*, 2R*). Correspondingly, (1R*, 2S*)means a 1:1 mixture of (1R, 2S) and (1S, 2R) and is the same as (1S*,2R*).

Example 1

1-(5,6-dichloro-3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidinehydrochloride

3.5 g (21.4 m mol) of 2-(pyrrolidin-1-ylmethyl)piperidinedihydrochloride (synthesized according to the method of U.S. Pat. No.2,684,965) was added to 85.6 ml (85.6 m mol) of 1N sodium hydroxidesolution cooled at from 0° C. to -5° C. The mixture was stirred for 30minutes, then 20 ml of methylene chloride containing 5.63 g of5,6-dichloro-3-oxoindan-1-carbonyl chloride (prepared by conventionalsynthesis from its corresponding acid made according to the procedurereported by Lahiri et al. in J. Indian Chem. Soc. 53, 1041 (1976)) wasadded dropwise to the mixture. The mixture was stirred for 90 minutes at-5° C. and then for 3 hours at room temperature.

After completion of the reaction, the reaction mixture was poured intoice water and extracted with diethyl ether. The extract was washed withsaturated aqueous sodium chloride solution and dried over anhydroussodium sulfate. The solvent was distilled off and the residue wassubjected to column chromatography to obtain 1.31 g of the desiredcompound by solution with a mixed solvent of ethyl acetate,triethylamine and ethanol (100;1;1). The product was dissolved inacetone, mixed with a 4N 1,4-dioxane solution of hydrogen chloride,evaporated down, and recrystallized from a mixed solvent of ethanol,acetone and diethyl ether (1;1;2), to give 1.24 g of the title compoundmelting at 239°-242° C. (dec).

Elemental analysis (%) C₂₀ H₂₅ Cl₃ N₂ O₂ Calcd C, 55.63; H, 5.84; N,6.49; Cl, 24.63 Found C, 55.11; H, 5.64; N, 6.39; Cl, 24.14.

Example 2

1-(5,6-dichloro-3-oxoindan-1-carbonyl)-(2S)-2-(pyrrolidin-1-ylmethyl)piperidinehydrochloride

15 ml of methylene chloride solution containing 3.13 g (11.88 m mol) of5,6-dichloro-3-oxoindan-1-carbonyl chloride was added dropwise at -10°C. to 15 ml of methylene chloride solution containing 1 g (5.94 m mol)of (2S)-2-(pyrrolidin-1-ylmethyl)piperidine and 1.82 ml (13.07 m mol) oftriethylamine. After the addition, the reaction mixture was stirred at-10° C. for 1 hour, poured into ice water and extracted with methylenechloride. The methylene chloride extract was washed with saturatedaqueous sodium chloride solution and dried over anhydrous sodiumsulfate. After evaporation of the solvent, a mixture of two opticallyactive isomers was obtained. Medium pressure liquid chromatography ofthe mixture using a mixed solvent of ethyl acetate and triethylamine(100;1) gave 0.65 g (27.7%) of one of the optically active isomers, E₁,eluted earlier, and 1.0 g (42.6%) of the other optically active isomer,E₂, eluted later.

Isomer E₁ was dissolved in acetone and mixed with a 4N 1,4-dioxanesolution of hydrogen chloride. After evaporation down, the residue wasrecrystallized from a mixed solvent of methanol, acetone and diethylether to afford colorless prisms melting at 243°-244° C. (dec), andshowing α!_(D) +36° (c=0.5, methanol).

In a similar way, Isomer E₂ in the form of the hydrochloride wasobtained as colorless needles melting at 194°-196° C. (dec), and showingα!-56° (c=0.5, methanol).

Isomer E₁ is 1-(1S)-5,6-dichloro-3-oxoindan-1-carbonyl!-(2S)-2-(pyrrolidin-1-ylmethyl)piperidine,and isomer E₂ is 1-(1R)-5,6-dichloro-3-oxoindan-1-carbonyl!-(2S)-2-(pyrrolidin-1-ylmethyl)piperidine.

Isomer E₁ hydrochloride Elemental analysis (%) C₂₀ H₂₅ Cl₃ N₂ O₂ CalcdC, 55.63; H, 5.84; N, 6.49; Cl, 24.63 Found C, 55.77; H, 5.88; N, 6.49;Cl, 24.65

Isomer E₂ hydrochloride Elemental analysis (%) C₂₀ H₂₅ Cl₃ N₂ O₂ CalcdC, 55.63; H, 5.84; N, 6.49; Cl, 24.63 Found C, 55.31; H, 5.87; N, 6.48;Cl, 22.38.

Example 3

1-(5,6-dichloro-3-oxoindan-1-carbonyl)-(2R)-2-(pyrrolidin-1-ylmethyl)piperidinehydrochloride

By following a procedure similar to that in Example 2, two opticalisomers were obtained as their hydrochlorides from 1.25 g of(2R)-2-(pyrrolidin-1-ylmethyl)piperidine, 1.5 g of triethylamine and1.96 g of 5,6-dichloro-3-oxoindan-1-carbonyl chloride. The productscomprised 0.45 g of the hydrochloride of one of the optically activeisomers (E₁), melting at 248°-250° C. (dec), and showing α!_(D) -37°(c=0.5, methanol), and 0.38 g of the hydrochloride of the other isomer(E₂), melting at 199°-201° C. (dec), and showing α!D +58° (c=0.5,methanol).

Isomer E₁ is 1-(1R)-5,6-dichloro-3-oxoindan-1-carbonyl!-(2R)-2-(pyrrolidin-1-ylmethyl)piperidine,and isomer E₂ is 1-(1S)-5,6-dichloro-3-oxoindan-1-carbonyl!-(2R)-2-(pyrrolidin-1-ylmethyl)piperidine.

Isomer E₁ hydrochloride Elemental analysis (%) C₂₀ H₂₅ Cl₃ N₂ O₂ CalcdC, 55.63; H, 5.84; N, 6.49; Cl, 24.63 Found C, 55.60; H, 5.78; N, 6.31;Cl, 24.49

Isomer E hydrochloride Elemental analysis (%) C₂₀ H₂₅ Cl₃ N₂ O₂ Calcd C,55.63; H, 5.84; N, 6.49; Cl, 24.63 Found C, 55.33; H, 5.90; N, 6.38; Cl,24.55.

Example 4

1-(1S*)-5,6-dichloro-3-oxoindan-1-carbonyl!-(2S*)-2-(pyrrolidin-1-ylmethyl)piperidinehydrochloride and 1-(1R*)-5,6-dichloro-3-oxoindan-1-carbonyl!-(2S*)-2-(pyrrolidin-1-ylmethyl)piperidinehydrochloride

Using a procedure similar to that in Example 1, the title compounds wereobtained from 5.0 g of 2-(pyrrolidin-1-ylmethyl)piperidinedihydrochloride, 5.3 g of 5,6-dichloro-3-oxoindan-1-carbonyl chlorideand 80 ml of 1N aqueous sodium hydroxide solution. By medium pressureliquid chromatographic separation using a mixed solvent of ethyl acetateand triethylamine (100;1), 0.85 g of one of the diastereoisomers. D₁,eluted earlier, and 0.88 g of the other diastereoisomer, D₂, elutedlater, were obtained. When each of these isomers was converted into itscorresponding hydrochloride by treatment with a 4N 1,4-dioxane solutionof hydrogen chloride, 0.97 g of the hydrochloride of isomer D₁, meltingat 253°-255° C. (dec) and 0.83 g of the hydrochloride of the otherisomer, D₂, melting at 228°-230° C. (dec) were obtained.

Diastereoisomer D₁ is 1-(1S*)-5,6-dichloro-3-oxoindan-1-carbonyl!-(2S*)-2-(pyrrolidin-1-ylmethyl)piperidineand diastereoisomer D₂ is 1-(1R*)-5,6-dichloro-3-oxoindan-1-carbonyl!-(2S*)-2-(pyrrolidin-1-ylmethyl)piperidine.

Diastereoisomer D₁ hydrochloride Elemental analysis (%) C₂₀ H₂₅ C₃ N₂ O₂Calcd C, 55.63; H, 5.84; N, 6.49; Cl, 24.63 Found C, 55.48; H, 5.85; N,6.47; Cl, 24.82

Diastereoisomer D₂ hydrochloride Elemental analysis (%) C₂ H₂₅ Cl₃ N₂ O₂Calcd C, 55.63; H, 5.84; N, 6.49; Cl, 24.63 Found C, 53.90; H, 6.00; N,6.12; Cl, 24.83.

Example 5

1-(3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidinehydrochloride

From 1.74 g of 2-(pyrrolidin-1-ylmethyl)piperidine, 2.21 g of3-oxoindan-1-carbonyl chloride and 2.16 ml of triethylamine, 1.21 g ofthe title compound was obtained, melting at 190°-215° C. (dec), using aprocedure similar to that in Example 2.

Elemental analysis (%) C₂₀ H₂₇ ClN₂₇ O₂ Calcd C, 66.19; H, 7.50; N,7.72; Cl, 9.77 Found C, 66.00; H, 7.62; N, 7.56; Cl, 9.56.

Example 6

1-(5-methyl-3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidinehydrochloride

From 2.7 g of 2-(pyrrolidin-1-ylmethyl)piperidine, 3.0 g of5-methyl-3-oxoindan-1-carbonyl chloride and 2.0 g of triethylamine, 2.1g of the title compound was obtained, melting at 153°-154° C. using aprocedure similar to that in Example 2.

Elemental analysis (%) C₂₁ H₂₉ ClN₂ O₂ Calcd C, 66.92; H, 7.76; N, 7.43;Cl, 9.41 Found C, 66.69; H, 7.80; N, 7.29; Cl, 9.23.

Example 7

1-(5-chloro-3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-yl-methyl)piperidinehydrochloride

To 100 ml of tetrahydrofuran solution containing 2.1 g of5-chloro-3-oxoindan-1-carboxylic acid and 1.5 ml of triethylamine, 1.1ml of ethyl chloroformate was added dropwise at -20° C. The reactionmixture was stirred for 20 minutes, 1.7 g of2-(pyrrolidin-1-ylmethyl)piperidine was added, and the mixture wasstirred for an additional 30 minutes. The reaction mixture was stirredfurther for 1 hour at room temperature. After completion of thereaction, the reaction mixture was poured into ice water and extractedwith diethyl ether. The extract was washed with water, dried overanhydrous sodium sulfate, and the solvent was distilled off. The residuewas subjected to silica gel column chromatography to obtain 0.8 g of thefree amine of the title compound by elution with a mixed solvent ofethyl acetate and triethylamine (50;1). By treatment with a 4N1,4-dioxane solution of hydrogen chloride, 0.6 g of the title compoundwas obtained, melting at 225°-230° C.

Elemental analysis (%) C₂₀ H₂₆ Cl₁₂ N₂ O₂ Calcd C, 60.46; H, 6.60; N,7.05; Cl, 17.84 Found C, 60.19; H, 6.80; N, 6.99; Cl, 17.64.

Example

1-(6-methoxy-3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidinehydrochloride

From 1.21 g of 2-(pyrrolidin-1-ylmethyl)piperidine dihydrochloride, 1.35g of 6-methoxy-3-oxoindan-1-carbonyl chloride and 2.79 ml oftriethylamine, 0.72 g of the title compound was obtained, melting at210°-228° C. (dec) using a procedure similar to that in Example 2.

Elemental analysis (%) C₂₁ H₂₉ ClN₂ O₃.1/2 H₂ O Calcd C, 62.75; H, 7.52;N, 6.97; Cl, 8.82 Found C, 62.51; H, 7.45; N, 6.83; Cl, 9.27.

Example 9

1-(4,5-dichloro-3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidinehydrochloride

From 1.18 g of 2-(pyrrolidin-1-ylmethyl)piperidine, 2.03 g of4,5-dichloro-3-oxoindan-1-carbonyl chloride and 1.47 ml oftriethylamine, 0.95 g of the title compound was obtained, melting at148°-150° C. (dec) using a procedure similar to that in Example 2.

Elemental analysis (%) C₂₀ H₂₅ Cl₃ N₂ O₂ Calcd C, 55.63; H, 5.84; N,6.49; Cl, 24.63 Found C, 55.11; H, 5.64; N, 6.39; Cl, 24.14.

Example 10

1-(6-hydroxy-3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidinehydrochloride

From 1.21 g of 2-(pyrrolidin-1-ylmethyl)piperidine dihydrochloride, 1.26g of 6-hydroxy-3-oxoindan-1-carbonyl chloride and 2.8 ml oftriethylamine, 0.1 g of the title compound was obtained, melting at220°-231° C. (dec), using a procedure similar to that in Example 2.

Elemental analysis (%) C₂₀ H₂₇ ClN₂ O₃ Calcd C, 63.40; H, 7.18; N, 7.39;Cl, 9.36 Found C, 63.60; H, 7.22; N, 7.84; Cl, 10.36.

Example 11

1-(5,6-dichloro-3-oxoindan-1-carbonyl)-2-(piperidinomethyl)piperidinehydrochloride

From 1.5 g of 2-(piperidinomethyl)piperidine dihydrochloride, 2.5 g of5,6-dichloro-3-oxoindan-1-carbonyl chloride and 45 ml of 1N aqueoussodium hydroxide solution, 1.1 g of the title compound was obtained,melting at 240°-245° C. (dec), using a procedure similar to that inExample 1.

Elemental analysis (%) C₂₁ H₂₇ Cl₃ N₂ O₃ Calcd C, 54.62; H, 5.89; N,6.07; Cl, 23.03 Found C, 54.60; H, 5.99; N, 6.00; Cl, 22.96.

Example 12

1-(1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)-2-(pyrrolidin-1-ylmethyl)piperidinehydrochloride

From 3.48 g of 2-(pyrrolidin-1-ylmethyl)piperidine dihydrochloride, 4.44g of 1,2,3,4-tetrahydro-4-oxo-1-naphthoyl chloride and 63.9 ml of 1Naqueous sodium hydroxide solution, 4.17 g of the title compound wasobtained, melting at 239°-242° C. (dec), using a procedure similar tothat in Example 1.

Elemental analysis (%) C₂₁ H₂₉ ClN₂ O₂ Calcd C, 66.92; H, 7.76; N, 7.43;Cl, 9.41 Found C, 66.34; H, 7.72; N, 7.24; Cl, 9.06.

Example 13

1-(6,7-dichloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)-2-(pyrrolidin-1-yl-methyl)piperidinehydrochloride

From 0.89 g of 2-(pyrrolidin-1-ylmethyl)piperidine, 1.61 g of6,7-dichloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl chloride and 11 ml oftriethylamine, 1.5 g of the title compound was obtained, melting at255°-257° C. (dec), using a procedure similar to that in Example 2.

Elemental analysis (%) C₂₁ H₂₇ Cl₃ N₂ O₂ Calcd C, 56.58; H. 6.10; N,6.28; Cl, 23.86 Found C, 55.86; H, 6.13; N, 6.16; Cl, 23.48.

Example 14

4,5-dihydro-6-oxo-4-2-(pyrrolidin-1-ylmethyl)piperidine-1-carbonyl!-6H-cyclopentab!thiophene hydrochloride

From 1.68 g of 2-(pyrrolidin-1-ylmethyl)piperidine, 2.2 g of4,5-dihydro-6-oxo-6H-cyclopenta b!thiophene-4-carbonyl chloride and 2.09ml of triethylamine, 1.02 of the title compound was obtained, melting at189°-218° C. (dec), using a procedure similar to that in Example 2.

Elemental analysis (%) C₁₈ H₂₅ ClN₂ O₂ S.1/2 H₂ O Calcd C, 57.20; H,6.68; N, 7.41; Cl, 9.38; S, 8.48 Found C, 56.91; H, 6.87; N, 7.13; Cl,9.09; S, 8.25.

Example 15

1-(5-nitro-3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidinehydrochloride

From 1.21 g of 2-(pyrrolidin-1-ylmethyl)piperidine dihydrochloride, 1.32g of 5-nitro-3-oxoindan-1-carbonyl chloride and 2.8 ml of triethylamine,0.05 g of the title compound was obtained, melting at 154°-160° C.(dec), using a procedure similar to that in Example 2.

Elemental analysis (%) C₂₀ H₂₆ ClN₃ O₄ Calcd C, 58.89; H, 6.43; N,10.30; Cl, 8.69 Found C, 58.59; H, 6.29; N, 10.17; Cl, 8.48.

Example 16

1-(indan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidine hydrochloride

From 2.36 g of 2-(pyrrolidin-1-ylmethyl)piperidine, 2.5 g ofindene-1-carbonyl chloride and 4.88 ml of triethylamine, 1.4 g of1-(indene-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidine was obtainedusing a procedure similar to that in Example 2. In a mixed solvent ofmethanol, water and ethanol (2;1;1), this compound was catalyticallyreduced with 10% palladium on carbon. After completion of the reduction,the catalyst was filtered off. After evaporation of the solvent, theresidue was treated with a 4N 1,4-dioxane solution of hydrogen chlorideto obtain 1.05 g of the title compound, melting at 218°-221° C.

Elemental analysis (%) C₂₀ H₂₇ ClN₂ Ol Calcd C, 69.25; H, 7.85; N, 8.08;Cl, 10.22

Found

C, 69.26; H, 8.01; N, 7.60; Cl, 10.89.

Example 17

4-(3,4-dichlorophenylacetyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholinehydrochloride

3-(Pyrrolidin-1-ylmethyl)thiomorpholine was generated from thecorresponding hydrochloride, prepared as described in the PreparativeExample which follows the Examples. A solution of 1.49 ml oftriethylamine and 1.0 g of 3-(pyrrolidin-1-ylmethyl)thiomorpholinedissolved in 50 ml of methylene chloride was cooled to 0° C. in anatmosphere of nitrogen with vigorous stirring. To the solution was addeddropwise 5 ml of methylene chloride containing 1.44 g of3,4-dichlorophenylacetyl chloride and the mixture was stirred at 3° C.for an hour and subsequently for 4 hours at room temperature.

After completion of the reaction, the reaction mixture was poured into asolution of sodium bicarbonate and extracted with ethyl acetate. Theextract was washed with water and dried over anhydrous magnesium sulfatefollowed by concentration of the solvent by distillation under reducedpressure. The residue was purified by column chromatography throughsilica gel and 1.39 g of the desired compound was obtained from thefractions eluted with a 3;1 mixture of ethyl acetate and methanol. Theproduct was dissolved in 20 ml of methylene chloride and mixed with amolar equivalent of a 4N 1,4-dioxane solution of hydrogen chloride. Themixture was concentrated and the residue was recrystallized from amixture of ethanol and acetone to afford the title compound as colorlesscrystals, melting at 230°-239° C. (dec.).

Elemental analysis (%) C₁₇ H₂₃ Cl₃ N₂ OS Calcd C, 49.83; H, 5.66; Cl,25.95; N, 6.84; S, 7.82 Found C, 49.69; H, 5.69; Cl, 25.52; N, 6.53; S,7.55.

Example 18

4-(3,4-dichlorophenylacetyl)-3-(pyrrolidin-1-ylmethyl)morpholinehydrochloride

The procedure described in Example 17 was repeated, but using 1.64 g of3-(pyrrolidin-1-ylmethyl)morpholine, 3.72 ml of triethylamine and 1.54 gof 3,4-dichlorophenylacetyl chloride, to afford 0.72 g of the titlecompound, melting at 268° (dec.).

Elemental analysis (%) C₁₇ H₂₃ Cl₃ N₂ O₂ Calcd C, 51.86; H, 5.89; N,7.11; Cl, 27.01 Found C, 51.68; H, 5.97; N, 7.20; Cl, 26.73.

Example 19

1-(3,4-dichlorophenylacetyl)-4-methyl-2-(pyrrolidin-1-ylmethyl-1)piperazinedihydrochloride

The procedure described in Example 17, but using 1.0 g of1-methyl-3-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride, 2.1 ml oftriethylamine and 0.8 g of 3,4-dichlorophenylacetyl chloride, to afford1.01 g of the title compound, melting at 223°-227° C. (dec.).

Elemental analysis (%) C₁₈ H₂₇ Cl₄ N₃ O.1/2 H₂₀ Calcd C, 47.80; H, 6.24;N, 9.29; Cl, 31.36 Found C, 47.63; H, 6.06; N, 9.40; Cl, 31.40.

Example 20

4-(4-methylphenylacetyl)-3-(pyrrolidin-1-ylmethyl)morpholinehydrochloride

To a solution of 1.33 g of 3-(pyrrolidin-1-ylmethyl)morpholinedihydrochloride in 30 ml of methylene chloride was added 1.5 ml of anaqueous solution containing 0.66 g of sodium hydroxide at 5° C. Afterthe mixture was stirred vigorously, the organic layer was separated anddried over anhydrous magnesium sulfate. To a solution of 0.84 g of4-methylphenylacetic acid, 0.78 ml of triethylamine and one drop ofN-methylmorpholine in 30 ml of tetrahydrofuran was added atetrahydrofuran solution containing 0.55 ml of ethyl chloroformate,followed by stirring at -20° to -15° C. for 20 minutes. To this stirredmixture was then added the previously prepared methylene chloridesolution of 3-(pyrrolidin-1-ylmethyl)morpholine. The mixture was stirredat the same temperature for 30 minutes and subsequently for an hour atroom temperature. After completion of the reaction, the reaction mixturewas washed with a saturated aqueous solution of sodium chloride anddried over anhydrous magnesium sulfate. After distilling off thesolvent, the residue was purified by column chromatography throughsilica gel and 0.56 g of the desired product was obtained from thefraction eluted with a 3;1 mixture of ethyl acetate and methanol. Theproduct was dissolved in methylene chloride and mixed with a molarequivalent of a 4N 1,4-dioxane solution of hydrogen chloride. Themixture was concentrated and recrystallized from a mixture of methanoland diethyl ether to afford the title compound, melting at 131° (dec.).

Elemental analysis (%) C₁₈ H₂₇ ClN₂ O₂.H₂ 0 Calcd C, 60.58; H, 8.19; N,7.85; Cl, 9.93 Found C, 61.16; H, 8.04; N, 7.78; Cl, 9.99.

Example 21

4-(4-methylthiophenylacetyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholinehydrochloride

The procedure described in Example 17 was repeated, but using 1.0 g of3-(pyrrolidin-1-ylmethyl)thiomorpholine, 1.38 ml of triethylamine and1.2 of 4-methylthiophenylacetyl chloride, to afford 1.38 g of the titlecompound, melting at 162°-166° C. (dec.).

Elemental analysis (%) C₁₈ H₂₆ ClN₂ OS₂ Calcd C, 55.86; H, 7.03; N,7.24; Cl, 9.16; S, 16.57 Found C, 55.48; H, 6.95; N, 6.96; Cl, 8.92; S,16.83.

Example 22

3-(pyrrolidin-1-ylmethyl)-4-(2-thienylacetyl)thiomorpholinehydrochloride

The procedure described in Example 17 was repeated, but using 1.0 g of3-(pyrrolidin-1-ylmethyl)thiomorpholine, 2.49 ml of triethylamine and1.03 g of 2-thienylacetyl chloride, to afford 0.37 g of the titlecompound, melting at 204°-206° C. (dec.).

Elemental analysis (%) C₁₅ H₂₃ ClN₂ OS₂ Calcd C, 51.93; H, 6.68; N,8.07; Cl, 10.22; S, 18.48 Found C, 51.85; H, 6.66; N, 8.10; Cl, 10.43;S, 18.24.

Example 23

3-(pyrrolidin-1-ylmethyl)-4-(2-thienylacetyl)morpholine hydrochloride

The procedure described in Example 17 was repeated, but using 0.88 g of3-(pyrrolidin-1-ylmethyl)morpholine, 2.0 ml of triethylamine and 0.45 gof 2-thienylacetyl chloride, to afford 0.71 g of the title compound,melting at 215° C. (dec.).

Elemental analysis (%) C₁₅ H₂₃ ClN₂ O₂ S Calcd C, 54.45; H, 7.01; N,8.47; Cl, 10.71; S, 9.69 Found C, 54.44; H, 7.08; N, 8.58; Cl, 10.72; S,9.61.

Example 24

1-(5,6-dichloro-3-oxoindan-1-carbonyl)-4-methyl-2-(pyrrolidin-1-ylmethyl)piperazinedihydrochloride

To a suspension of 2.0 g of 4-methyl-2-(pyrrolidin-1-ylmethyl)piperazinetrihydrochloride in 150 ml of methylene chloride was added 4.3 ml oftriethylamine with vigorous stirring in an atmosphere of nitrogen. Afterstirring for 20 minutes, the mixture was cooled to -10° C. in an ice andsalt bath and 50 ml of methylene chloride solution containing 1.9 g of5,6-dichloro-3-oxoindan-1-carbonyl chloride was added dropwise to it.The reaction mixture was stirred at -10° C. for an hour and a half andsubsequently at room temperature for two hours and a half and pouredinto a saturated aqueous solution of sodium bicarbonate. The resultingaqueous mixture was extracted with diethyl ether and the extract waswashed with a saturated aqueous solution of sodium chloride followed bydrying over anhydrous magnesium sulfate and distilling off the solvent.The residue was purified by column chromatography through silica gel and1.60 g of the desired compound was obtained from the fractions elutedwith a 10:3 mixture of ethyl acetate and triethylamine. To a solution ofthe product dissolved in methylene chloride was added a two molarquantity of a 4 N 1,4-dioxane solution of hydrogen chloride and themixture was concentrated. The residue was recrystallized from a mixtureof ethanol and acetone to afford the title compound, melting at250°-255° C. (dec.).

Elemental analysis (%) C₂₀ H₂₇ Cl₄ N₃ O₂.1/2 H₂ O

Calcd

C, 48.80; H, 5.73; N, 8.54; Cl, 28.81

Found

C, 49.20; H, 5.73; N, 8.54; Cl, 29.05.

Example 25

4-methyl-1-(5-methyl-3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperazinedihydrochloride

The procedure described in Example 24 was repeated, but using 1.0 g of1-methyl-3-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride, 2.1 ml oftriethylamine and 0.75 g of 5-methyl-3-oxoindan-1-carbonyl chloride, toafford 0.84 g of the title compound, melting at 220°-223° C. (dec.).

Elemental analysis (%) C₂₁ H₃₁ Cl₂ N₃ O₂.1/2 H₂ O Calcd C, 57.66; H,7.37; No 9.61; Cl, 16.21 Found C, 57.86; H, 7.42; N, 9.32; Cl, 16.07.

Example 26

4-methyl-1-(3-oxoindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperazinedihydrochloride

The procedure described in Example 24 was repeated, but using 3.21 g of1-methyl-3-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride, 6.9 ml oftriethylamine and 4.5 g of 3-oxoindan-1-carbonyl chloride, to afford1.45 g of the title compound, melting at 252°-255° C. (dec.).

Elemental analysis (%) C₂₀ H₂₉ Cl₂ N₃ O₂.1/2 H₂ O Calcd C, 56.74; H,7.14; N, 9.92; Cl, 16.75 Found C, 56.57; H, 7.25; N, 9.69; Cl, 16.56.

Example 27

1-(5,6-dichloroindan-1-carbonyl)-4-methyl-2-(pyrrolidin-1ylmethyl)piperazinedihydrochloride

The procedure described in Example 24 was repeated, but using 1.67 g of1-methyl-3-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride, 3.6 ml oftriethylamine and 1.5 g of 5,6-dichloroindan-1-carbonyl chloride, toafford 1.54 g of the title compound, melting at 245°-250° C.

Elemental analysis (%) C₂₀ H₂₉ Cl₄ N₃.1/2 H₂ O Calcd C, 50.23; H, 6.32;N, 8.79; Cl, 29.65 Found C, 50.09; H, 6.23; N, 8.74; Cl, 29.56.

Example 28

1-(6,7-dichloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)-4-methyl-2-(pyrrolidin-1-ylmethyl)piperazinedihydrochloride

The procedure described in Example 24 was repeated, but using 1.0 g of1-methyl-3-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride, 2.1 ml oftriethylamine and 1.0 g of6,7-dichloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl chloride, to afford0.97 g of the title compound, melting at 275°-278° C. (dec.).

Elemental analysis (%) C₂₁ H₂₉ Cl₄ N₃ O₂.1/2 H₂ O Calcd C, 49.82; H,5.97; N, 8.30; Cl, 28.01 Found C, 50.12=H, 5.83; N, 8.32; Cl, 27.90.

Example 29

1-(6-chloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)-4-methyl-2-(pyrrolidin-1-ylmethyl)piperazinedihydrochloride The procedure described in Example 24 was repeated, butusing 1.0 g of 1-methyl-3-(pyrrolidin-1-ylmethyl)piperazinetrihydrochloride, 2.1 ml of triethylamine and 0.87 g of 6-chloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl chloride, to afford 0.9 2 g of thetitle compound, melting at 268°-274° C. (dec.).

Elemental analysis (%) C₂₁ H₃₀ Cl₃ N₃ O₂ Calcd C, 54.50; H, 6.53; No9.08; Cl, 22.98 Found C, 54.68; H, 6.36; N, 9.01; Cl, 22.64.

Example 30

4-(5,6-dichloro-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)morpholinehydrochloride

The procedure described in Example 24 was repeated, but using 0.88 g of3-(pyrrolidin-1-ylmethyl)morpholine, 2.0 ml of triethylamine and 1.0 gof 5,6-dichloro-3-oxo-indan-1-carbonyl chloride, to afford 0.66 g of thetitle compound, melting at 250°-257° C. (dec.).

Elemental analysis. (%) C₁₉ H₂₃ Cl₃ N₂ O₃.H₂ O Calcd C, 50.51; H, 5.58;N, 6.20; Cl, 23.50 Found C, 50.43; H, 5.58; N, 6.27; Cl, 23.72.

Example 31

4-(3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)morpholinehydrochloride

The procedure described in Example 24 was repeated, but using 0.86 g of3-(pyrrolidin-1-ylmethyl)morpholine, 1.96 ml of triethylamine and 0.89 gof 3-oxoindan-1-carbonyl chloride, to afford 0.35 g of the titlecompound, melting at 260°-265° C. (dec.).

Elemental analysis (%) C₁₉ H₂₅ ClN₂ O₃ Calcd C, 62.54; H, 6.91; N, 7.68;Cl, 9.72 Found C, 62.26; H, 7.02; N, 7.73; Cl, 9.75.

Example 32

4-(5-methyl-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)morpholinehydrochloride

The procedure described in Example 24 was repeated, but using 0.89 g of3-(pyrrolidin-1-ylmethyl)morpholine, 2.2 ml of triethylamine and 0.83 gof 5-methyl-3-oxoindan-1-carbonyl chloride, to afford 0.23 g of thetitle compound, melting at 225°-230° C.

Elemental analysis (%) C₂₀ H₂₇ ClN₂ O₃ Calcd C, 63.40; H, 7.18; N, 7.39;Cl, 9.36 Found C, 63.50; H, 7.09; N, 7.40; Cl, 9.49.

Example 33

4-(5-chloro-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)morpholinehydrochloride

The procedure described in Example 24 was repeated, but using 0.89 g of3-(pyrrolidin-1-ylmethyl)morpholine, 2.0 ml of triethylamine and 0.91 gof 5-chloro-3-oxoindan-1-carbonyl chloride, to afford 0.83 g of thetitle compound, melting at 220°-229° C. (dec.).

Elemental analysis (%) C₁₉ H₂₄ Cl₂ N₂ O₃ Calcd C, 57.15; H, 6.06; N,7.02; Cl, 17.76 Found C, 56.90; H, 6.01; N, 7.00; Cl, 17.55.

Example 34

4-(5,6-dichloro-3-oxoindan-1-carbonyl)-3-(morpholinomethyl)morpholinehydrochloride

The procedure described in Example 24 was repeated, but using 1.25 g of3-(morpholinomethyl)morpholine, 2.67 ml of triethylamine and 1.11 g of5,6-dichloro-3-oxoindan-1-carbonyl chloride, to afford 0.7 g of thetitle compound, melting at 210°-216° C. (dec.).

Elemental analysis (%) C₁₉ H₂₃ Cl₃ N₂ O₄ Calcd C, 50.74; H, 5.15; N,6.23; Cl, 23.65 Found C, 50.43; H, 5.04; N, 6.16; Cl, 23.40.

Example 35

4-(5-chloro-3-oxoindan-1-carbonyl)-3-(dimethylaminomethyl)morpholinehydrochloride

The procedure described in Example 24 was repeated, but using 0.90 g of3-dimethylaminomethylmorpholine, 2.3 ml of triethylamine and 1.03 g of5-chloro-3-oxoindan-1-carbonyl chloride, to afford 1.03 g of the titlecompound, melting at 230°-240° C.

Elemental analysis (%) C₁₇ H₂₂ Cl₂ N₂ O₃ Calcd C, 54.70; H, 5.94; N,7.50; Cl, 19.00 Found C, 54.36; H, 6.28; N, 7.28; Cl, 19.21.

Example 36

4-(5,6-dichloro-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholinehydrochloride

The procedure described in Example 24 was repeated, but using 0.6 g of3-(pyrrolidin-1-ylmethyl)thiomorpholine, 0.6 g of triethylamine and 1.0g of 5,6-dichloro-3-oxoindan-1-carbonyl chloride, to afford 0.39 g ofthe title compound, melting at 215°-223° C.

Elemental analysis (%) C₁₉ H₂₃ Cl₃ N₂ O₂ S.H₂ O Calcd C, 48.74; H, 5.34;N, 5.99; S, 6.85 Found C, 48.46; H, 5.34; N, 5.90; S, 7.02.1

Example 37

4-(5-methyl-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholinehydrochloride

The procedure described in Example 24 was repeated, but using 0.92 g of3-(pyrrolidin-1-ylmethyl)thiomorpholine, 1.64 ml of triethylamine and1.66 g of 5-methyl-3-oxoindan-1-carbonyl chloride, to afford 1.35 g ofthe title compound, melting at 232°-234° C.

Elemental analysis (%) C₂₀ H₂₇ ClN₂ O₂ S Calcd C, 60.82; H, 6.89; N,7.09; Cl, 8.97; S, 8.11 Found C, 60.57; H, 6.77; N, 7.06; Cl, 8.69; S,8.38

Example 38

4-(5-chloro-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholinehydrochloride

The procedure described in Example 24 was repeated, but using 3.7 g of3-(pyrrolidin-1-ylmethyl)thiomorpholine, 3.42 ml of triethylamine and4.56 g of 5-chloro-3-oxoindan-1-carbonyl chloride, to afford 2.8 g ofthe title compound, melting at 200°-205° C. (dec.).

Elemental analysis (%) C₁₉ H₂₄ Cl₂ N₂ O₂ S Calcd C, 54.94; H, 5.82; N,6.74; Cl, 17.07; S, 7.72 Found C, 54.99=H, 6.02; N, 6.65; Cl, 16.82; S,7.63.

Example 39

4-(6-methoxy-3-oxoindan-1-carbonyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholinehydrochloride

The procedure described in Example 24 was repeated, but using 0.97 g of3-(pyrrolidin-1-ylmethyl)thiomorpholine, 1.39 ml of triethylamine and1.23 g of 6-methoxy-3-oxoindan-1-carbonyl chloride, to afford 0.9 g ofthe title compound, melting at 225°-233° C.

Elemental analysis (%) C₂₀ H₂₇ ClN₂ O₃ S Calcd C, 58.45; H, 6.62; N,6.82; Cl, 8.63; S, 7.80 Found C, 58.55; H, 6.85; N, 6.59; Cl, 8.50; S,7.62.

Example 40

4,5-dihydro-6-oxo-4-3-(pyrrolidin-1-ylmethyl)thiomorpholine-1-carbonyl!-6H-cyclopentab!thiophene hydrochloride

The procedure described in Example 24 was repeated, but using 0.96 g of3-(pyrrolidin-1-ylmethyl)thiomorpholine, 1.39 ml of triethylamine and1.0 g of 4,5-dihydro-6-oxo-6H-cyclopenta b!thiophene-4-carbonylchloride, to afford 0.5 g of the title compound, melting at 204°-223° C.

Elemental analysis (%) C₁₇ H₂₃ ClN₂ O₂ S₂.1/2 H₂ O Calcd C, 51.57; H,6.11; N, 7.07; Cl, 8.95; S, 16.19 Found C, 51.71; H, 6.09; N, 7.08; Cl,8.76; S, 16.30.

Example 41

4-(1S*)-5,6-dichloroindan-1-carbonyl!-(3S*)-3-(pyrrolidin-1-ylmethyl)thiomorpholinehydrochloride, and 4-(1R*)-5,6-dichloroindan-1-carbonyl!-(3S*)-3-(pyrrolidin-1-ylmethyl)thiomorpholinehydrochloride

The procedure described in Example 24 was repeated, but using 0.72 g of3-(pyrrolidin-1-ylmethyl)thiomorpholine, 0.8 ml of triethylamine and1.08 g of 5,6-dichloroindan-1-carbonyl chloride, to afford the titlecompounds as diastereoisomers, which were separated by columnchromatography under medium pressure using a mixed solvent of ethylacetate and triethylamine (100;1). There were obtained 0.57 g ofdiastereoisomer D₁ in the earlier effluent and 0.19 g of diastereoisomerD₂ in the later effluent. Each diastereoisomer was converted todiastereoisomer D₁ hydrochloride melting at 220°-230° C. anddiastereoisomer D₂ hydrochloride, melting at 230°-242° C., respectively.

Diastereoisomer D₁ is 4-(18*)-5,6-dichloroindan-1-carbonyl!-(3S*)-3-(pyrrolidin-1-ylmethyl)thiomorpholine,and diastereoisomer D₂ is 4-(1R*)-5,6-dichloroindan-1-carbonyl!-(3S*)-3-(pyrrolidin-1-ylmethyl)thiomorpholine

Diastereoisomer D₁ hydrochloride Elemental analysis (%) C ₁₉ H₂₅ Cl₃ N₂OS Calcd C, 52.36; H, 5.78; N, 6.43; Cl, 24.40; 7.36 Found C, 52.25; H,5.70; N, 6.50; Cl, 24.61; 7.35

Diastereoisomer D₂ hydrochloride Elemental analysis (%) C₁₉ H₂₅ Cl₃ N₂OS Calcd C, 52.36; H, 5.78; N, 6.43; Cl, 24.40; S, 7.36 Found C, 52.28;H, 5.70; N, 6.60; Cl, 24.52; S, 7.29.

Example 42

4-(5,6-dichloro-3-oxoindan-1-carbonyl)-3-(piperidinomethyl)thiomorpholinehydrochloride

The procedure described in Example 24 was repeated, but using 0.9 g of3-(piperidinomethyl)thiomorpholine, 1.0 g of triethylamine and 1.5 g of5,6-dichloro-3-oxoindan-1-carbonyl chloride, to afford 0.45 g of thetitle compound, melting at 146°-155° C.

Elemental analysis C%) C₂₀ H₂₅ Cl₃ N₂ O₂ S.H₂ O Calcd C, 49.80; H, 5.60;N, 5.81; Cl, 22.07; S, 6.65 Found C, 49.54; H, 5.57; N, 5.81; Cl, 22.35;S, 6.70.

Example 43

4-(1s*)-6,7-dichloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl!-(3S*)-3-(pyrrolidin-1-ylmethyl)thiomorpholinehydrochloride, and 4-(1R*)-6,7-dichloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl!-(3S*)-3-(pyrrolidin-1-ylmethyl)thiomorpholine hydrochloride

According to a manner similar to that of Example 24, the reactionproducts prepared from 3.7 g of 3-(pyrrolidin-1-ylmethyl)thiomorpholine,3.4 ml of triethylamine and 5.5 g of6,7-dichloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl chloride wereseparated by column chromatography under medium pressure using a mixedsolvent of ethyl acetate and triethylamine (100;1). Diastereoisomer D₁(1.9 g) was obtained from the fractions eluted earlier anddiastereoisomer D₂ (2.8 g) from the fractions eluted later. Each isomerwas converted into diastereoisomer D₁ hydrochloride, melting at263°-264° C. and diastereoisomer D₂ hydrochloride, melting at 264°-265°C., respectively.

Diastereoisomer D₁ is 4- (1S*)-6,7-dichloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl!-(3S*)-3-(pyrrolidin-1-ylmethyl)thiomorpholinehydrochloride, and diastereoisomer D₂ is 4-(1R*)-6,7-dichloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl!-(3S*)-3-(pyrrolidin-1-ylmethyl)thiomorpholinehydrochloride

Diastereoisomer D₁ hydrochloride Elemental analysis (%) C₂₀ H₂₅ N₂ O₂Cl₃ S Calcd C, 51.79; H, 5.43; N, 6.04; Cl, 22.93; S, 6.91 Found C,51.57; H, 5.70; N, 5.90; Cl, 23.02; S, 6.85

Diastereoisomer D₂ hydrochloride Elemental analysis (%) C₂₀ H₂₅ N₂ O₂Cl₃ S Calcd C, 51.79; H, 5.43; N, 6.04; Cl, 22.93; S, 6.91 Found C,51.79; H, 5.69; N, 6.05; Cl, 22.861 S, 6.86.

Example 44

4-(6-chloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)-3-(pyrrolidin-1-ylmethyl)thiomorpholinehydrochloride

The procedure described in Example 24 was repeated, but using 1.0 g of3-(pyrrolidin-1-ylmethyl)thiomorpholine, 1.38 ml of triethylamine and1.5 g of 6-chloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl chloride, toafford 1.76 g of the title compound, melting at 195°-200° C.

Elemental analysis (%) C₂₀ H₂₆ N₂ O₂ Cl₂ S.H₂ O Calcd C, 53.69; H, 6.30;N, 6.26; Cl, 15.85; S, 7.17 Found C, 53.72; H, 6.04; N, 6.28; Cl, 15.58;S, 7.07.

Example 45

4-(6,7-dichloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl)-4-(piperidinomethyl)thiomorpholinehydrochloride

The procedure described in Example 24 was repeated, but using 2.0 g of3-(piperidinomethyl)thiomorpholine, 2.2 ml of triethylamine and 3.52 gof 6,7-dichloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl chloride, to afford3.67 g of the title compound, melting at 245°-254° C. (dec.).

Elemental analysis (%) C₂₁ H₂₇ N₂ O₂ Cl₃ S Calcd C, 52.78; H, 5.70; N,5.86; Cl, 22.26; S, 6.71 Found C, 53.00; H, 6.01; N, 5.60; Cl, 21.93; S,6.47.

Example 46

4-(5,6-dichloro-3-oxoindan-1-carbonyl)-(3R)-3-(pyrrolidin-1-ylmethyl)thiomorpholineA solution (15 ml) of 3.0 g of 5,6-dichloro-3-oxoindan-1-carboxylic acidchloride in methylene chloride was dropwise added at -10° C. to a 15 mlof methylene chloride solution of(3R)-3-(pyrrolidin1-ylmethyl)thiomorpholine (1 g) and triethylamine (2ml). The reaction mixture was stirred for 1 hour at -10° C. and pouredinto ice-water. The mixture was extracted with methylene chloride. Then,the extract was washed with a saturated solution of sodium chloride anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure to give a mixture of two optical isomers. This mixturewas subjected to medium pressure liquid chromatography and eluted usinga mixed solvent of ethyl acetate and triethylamine (100;1), to yield 0.8g of an optical isomer E₁ (oil) as a first fraction and 1.0 g of anoptical isomer E₂ (oil) as a second fraction. Isomer E₁ is the (1S)isomer, and isomer E₂ is the (1R) isomer.

Example 47

1-(5,6-dichloroindan-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidinehydrochloride

From 1.18 g of 2-(pyrrolidin-1-ylmethyl)piperidine, and 1.87 g of5,6-dichloroindan-1-carbonyl chloride, 0.51 g of the title compound wasobtained, melting at 245°-250° C., using a procedure similar to that inExample 1.

Elemental analysis (%) C₂₀ H₂₇ Cl₃ N₂ O Calcd C, 57.50; H, 6.51; N,6.70; Cl, 25.46 Found C, 57.25; H, 6.58; N, 6.62; Cl, 25.25.

Example 48

1-(5,6-dichloro-3-oxoindan-1-carbonyl)-2-(morpholinomethyl)piperidinehydrochloride

From 0.93 g of 2-(morpholinomethyl)piperidine, and 1.00 g of5,6-dichloro-3-oxoindan-1-carbonyl chloride, 0.85 g of the titlecompound was obtained, melting at 235°-240° C., using a proceduresimilar to that in Example 1.

Elemental analysis (%) C₂₀ H₂₅ Cl₃ N₂ O₃ Calcd C, 53.65; H, 5.63; N,6.26; Cl, 23.75 Found C, 53.47; H, 5.72; N, 6.31=Cl, 23.57.

Example 49

4-2-(3,4-dichlorophenyl)propionyl!-3-(pyrrolidin-1-ylmethyl)thiomorpholinehydrochloride

From 1.86 g of 3-(pyrrolidin-1-ylmethyl)thiomorpholine, and 2.4 g of2-(3,4-dichlorophenyl)propionyl chloride, 0.71 g of the title compoundwas obtained, melting at 224°-230° C., using a procedure similar to thatin Example 1.

Elemental analysis (%) C₁₈ H₂₅ Cl₃ N₂ OS Calcd C, 51.00; H, 5.90; N,6.61; Cl, 25.15; S, 7.56 Found C, 51.18; H, 6.05; N, 6.60; Cl, 25.57; S,7.22.

Pharmaceutical Example.

Capsule

The compound of Example 36 (1 mg) was triturated in to a 1;50 compoundwith lactose, and the resulting powder was again triturated in to a 1;20powder with lactose, giving Powder A.

100 mg of Powder A and 0.5 mg of magnesium stearate were packed in tocapsules (No. 5).

Preparative Example

3-(pyrrolidin-1-ylmethyl)thiomorpholine dihydrochloride

(a) 4-(t-butoxycarbonyl)thiomorpholine-3-carboxylic acid

Triethylamine (23.6 ml) was added at 0° C. to a solution ofDL-thiomorpholine-3-carboxylic acid (5 g) in 40 ml of a 1;1 mixture of1,4-dioxane and water. Thereafter, di-t-butyl dicarbonate (8.16 g) wasadded and the reaction mixture was stirred for 30 minutes at 0° C. andfor 3 hours at room temperature. The solvent was evaporated underreduced pressure and the residue was dissolved in 100 ml of ethylacetate. The pH of the reaction solution was adjusted to 4 usingsaturated citric acid solution and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was recrystallized from hexane/ethylacetate to yield 6.0 g (71%) of4-(t-butoxycarbonyl)thiomorpholine-3-carboxylic acid.

(b) 3-(pyrrolidine-1-carbonyl)thiomorpholine

Triethylamine (3.1 mi), followed by a solution of pyrrolidine (2.0 ml)in 10 ml of tetrahydrofuran was added at 0° C. under a stream ofnitrogen to a solution of 5.0 g of4-(t-butoxycarbonyl)thiomorpholine-3-carboxylic acid in 100 ml oftetrahydrofuran. After the mixture had been stirred for 1 hour, asolution of 3.6 g of ethyl cyanophosphate in 10 ml of tetrahydrofuranwas added to the mixture and the mixture was stirred for 5 hours. Waterwas added to the reaction mixture and the mixture was extracted withethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate and the solvent was concentrated under reduced pressure. Theresidue was recrystallized from ethyl acetate/hexane to yield 4.61 g(74%) of 4-(t-butoxycarbonyl)-3-(pyrrolidine-1-carbonyl)thiomorpholine.

4-(t-butoxycarbonyl)-3-(pyrrolidine-1-carbonyl)thiomorpholine (3.2 g)was dissolved in 50 ml of methanol. A 4N 1,4-dioxane solution ofhydrogen chloride (13.1 ml) was added, and the solution was condensed toyield white crystals. These crystals was recrystallized from ethanol anddiethyl ether to give 2.47 g (96%) of3-(pyrrolidine-1-carbonyl)thiomorpholine monohydrochloride.

A 1N aqueous sodium hydroxide solution (12.5 ml) was added to a mixtureof 2.47 g of 3-(pyrrolidine1-carbonyl)thiomorpholine monohydrochlorideand 20 ml of methylene chloride. The organic layer was extracted anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure to yield 1.75 g (83%) of3-(pyrrolidine-1-carbonyl)thiomorpholine

(c) 3-(pyrrolidin-1-ylmethyl)thiomorpholine dihydrochloride

A solution of 1.6 g of 3-(pyrrolidine-1-carbonyl)thiomorpholine in 200ml of tetrahydrofuran was added dropwise to a mixture of 1o0 g oflithium aluminum hydride and 100 ml of tetrahydrofuran under ice-coolingand a stream of nitrogen. Excess lithium aluminum hydride was decomposedusing 15 g of sodium sulfate decahydrate. Celite filtration usingmethylene chloride was carried out. The solvent was concentrated underreduced pressure to yield 1.37 g (93%) of3-(pyrrolidin-1-ylmethyl)thiomorpholine.

A mixture of 260 mg of 3-(pyrrolidin-1-ylmethyl)thiomorpholine and 5 mlof 1,4-dioxane was treated with 150 μl of 4N 1,4-dioxane solution ofhydrogen chloride. The solvent was evaporated under reduced pressure toyield 354 mg (98%) of 3-(pyrrolidin-1-ylmethyl)thiomorpholinedihydrochloride, melting at 218°-220° C.

Elemental Analysis (%) C₉ H₂₀ N₂ SCl₂ Calcd C, 41.70; H, 7.78; No 10.80;S, 12.37; Cl, 27.35 Found C, 41.57; H, 8.04; N, 10.61; S, 12.25; Cl,27.30.

We claim:
 1. A compound of the formula (I) ; ##STR6## and stereoisomericforms thereof in which,R¹ and R² are the same or different and each isselected from the group consisting of a hydrogen atom and C₁ -C₆ alkylgroups, or R¹ and R² together with the nitrogen atom to which they areattached form a heterocyclic ring; E is an oxygen atom; ring A isselected from the group consisting of unsubstituted aryl rings;unsubstituted heteroaryl rings; aryl rings substituted with at least onesubstituent of Group (i); and heteroaryl rings substituted with at leastone substituent of Group (i); said at least one substituent of Group (i)is selected from the group consisting of halogen atoms, C₁ -C₆ alkylgroups, halogenated C₁ -C₆ alkyl groups, C₁ -C₆ alkoxy groups,halogenated C₁ -C₆ alkoxy groups, C₁ -C₆ alkylthio groups, aryl groups,acyl groups, nitro groups, and hydroxy groups; R³ and R⁴ togetherrepresent a group of formula (IV):

    --(CR.sup.a R.sup.b).sub.m --C(═Y)--                   (IV)

wherein each of R^(a) and R^(b) represents hydrogen or a C₁ -C₃ alkylgroup, m represents 1, 2, or 3, and Y represents two hydrogen atoms oran oxygen atom; and pharmaceutically acceptable salts thereof.
 2. Thecompounds and salts of claim 1, whereinR¹ and R² are the same ordifferent and each of R¹ and R² is a C₁ -C₆ alkyl group, or R¹ and R²together with the nitrogen atom to which they are attached form a 5- or6-membered heterocyclic ring; ring A is selected from the groupconsisting of aryl rings; heteroaryl rings; aryl rings substituted withat least one substituent of Group (ii); and heteroaryl rings substitutedwith at least one substituent of Group (ii); said at least onesubstituted of Group (ii) is selected from the group consisting ofhalogen atoms, halogenated C₁ -C₆ alkyl groups, and C₁ -C₆ alkyl groups;and m represents 1, or
 2. 3. The compounds and salts of claim 1, whereinring A is selected from the group consisting of aryl rings and arylrings substituted with at least one substituent selected from the groupconsisting of halogen atoms and C₁ -C₃ alkyl groups.
 4. The compoundsand salts of claim 1,wherein each of R^(a) and R^(b) represents ahydrogen atom, and m represents 1, or
 2. 5. A pharmaceutical compositioncomprising an effective analgesic amount of a compound of formula (I):##STR7## and stereoisomeric forms thereof in which,R¹ and R² are thesame or different and each is selected from the group consisting of ahydrogen atom and C₁ -C₆ alkyl groups, or R¹ and R² together with thenitrogen atom to which they are attached form a heterocyclic ring; E isan oxygen atom; ring A is selected from the group consisting ofunsubstituted aryl rings; unsubstituted heteroaryl rings; aryl ringssubstituted with at least one substituent of Group (i); and heteroarylrings substituted with at least one substituent of Group (i); said atleast one substituent of Group (i) is selected from the group consistingof halogen atoms, C₁ -C₆ alkyl groups, halogenated C₁ -C₆ alkyl groups,C₁ -C₆ alkoxy groups, halogenated C₁ -C₆ alkoxy groups, C₁ -C₆ alkylthiogroups, aryl groups, acyl groups, nitro groups, and hydroxy groups; R³and R⁴ together represent a group of formula (IV):

    --(CR.sup.a R.sup.b).sub.m --C(═Y)--                   (IV)

wherein each R^(a) and R^(b) represents hydrogen or a C₁ -C₃ alkylgroups, m represents 1, 2, or 3, and Y represents two hydrogen atoms oran oxygen atom; or a pharmaceutically acceptable salt thereof; togetherwith a pharmaceutically acceptable carrier.
 6. A method for the reliefof pain, which comprises administering to a susceptible animal aneffective analgesic amount of an analgesic drug, wherein said analgesicdrug comprises at least one compound which is a compound of formula (I):##STR8## and stereoisomeric forms thereof in which,R¹ and R² are thesame or different and each is selected from the group consisting of ahydrogen atom and C₁ -C₆ alkyl groups, R¹ and R² together with thenitrogen atom to which they are attached form a heterocyclic ring; E isan oxygen atom; ring A is selected from the group consisting ofunsubstituted aryl rings; unsubstituted heteroaryl rings; aryl ringssubstituted with at least one substituent of Group (i); and heteroarylrings substituted with at least one substituent of Group (i); said atleast one substituent of Group (i) is selected from the group consistingof halogen atoms, C₁ -C₆ alkyl groups, halogenated C₁ -C₆ alkyl groups,C₁ -C₆ alkoxy groups, halogenated C₁ -C₆ alkoxy groups, C₁ -C₆ alkylthiogroups, aryl groups, acyl groups, nitro groups, and hydroxy groups; R³and R⁴ together represent a group of formula (IV):

    --(CR.sup.a R.sup.b).sub.m --C(═Y)--                   (IV)

wherein each of R^(a) and R^(b) represents hydrogen or a C₁ --C₃ alkylgroup, m represents 1, 2, or 3, and Y represents two hydrogen atoms oran oxygen; or a pharmaceutically acceptable salt thereof.
 7. Thecompounds and salts of claim 1, wherein said compound is4-(3-oxo-5,6-dichloro-1-indanecarbonyl)-3-(1-pyrrolidinylmethyl)morpholine8. The compounds and salts of claim 1, wherein said compound is4-(4-oxo-6,7-dichloro-1,2,3,4-tetrahydro-1-naphtholyl)-3-(1-pyperidylmethyl)morpholine.9. The composition of claim 5, wherein the compound is selected from thegroup consisting of4-(3-oxo-5,6-dichloro-1-indanecarbonyl)-3-(1-pyrrolidinylmethyl)morpholineand4-(4-oxo-6,7-dichloro-1,2,3,4-tetrahydro-1-naphthoyl)-3-(1pyperidylmethyl)morpholine.10. The method of claim 6, wherein the compound is selected from thegroup consisting of4-(3-oxo-5,6-dichloro-1-indanecarbonyl)-3-(1-pyrrolidinylmethyl)morpholineand4-(4-oxo-6,7-dichloro-1,2,3,4-tetrahydro-1-naphthoyl)-3-(1pyperidylmethyl)morpholine.11. A compound of the formula (I): ##STR9## and stereoisomeric formsthereof in which,R¹ and R² are the same or different and each isselected from the group consisting of a hydrogen atom and C₁ -C₆ alkylgroups, or R¹ and R² together with the nitrogen atom to which they areattached form a heterocyclic ring; E is selected from the groupconsisting of an unsubstituted imino group, and an imino groupsubstituted with a substituent selected from the group consisting of C₁-C₆ alkyl groups and aralkyl groups; ring A is selected from the groupconsisting of unsubstituted aryl rings; unsubstituted heteroaryl rings;aryl rings substituted with at least one substituent of Group (i); andheteroaryl rings substituted with at least one substituent of Group (i);said at least one substituent of Group (i) is selected from the groupconsisting of halogen atoms, C₁ -C₆ alkyl groups, halogenated C₁ -C₆alkyl groups, C₁ -C₆ alkoxy groups, halogenated C₁ -C₆ alkoxy groups, C₁-C₆ alkylthio groups, aryl groups, acyl groups, nitro groups, andhydroxy groups; R³ represents a hydrogen atom or a C₁ -C₆ alkyl group,R⁴ represents a hydrogen atom, or R³ and R⁴ together represent a groupof formula (IV):

    --(CR.sup.a R.sup.b).sub.m --C(═Y)--                   (IV)

wherein each of R^(a) and R^(b) represents hydrogen or a C₁ -C₃ alkylgroup; m represents 1,2, or 3, and Y represents two hydrogen atoms or anoxygen atom; and pharmaceutically acceptable salts thereof.
 12. Thecompounds and salts of claim 11, whereinR¹ and R² are the same ordifferent and each of R¹ and R² is a C₁ -C₆ alkyl group, or R¹ and R²together with the nitrogen atom to which they are attached form a 5- or6-membered heterocyclic ring; ring A is selected from the groupconsisting of aryl rings; heteroaryl rings; aryl rings substituted withat least one substituent of Group (ii); and heteroaryl rings substitutedwith at least one substituent of Group (ii); said at least onesubstituent of Group (ii) is selected from the group consisting ofhalogen atoms, halogenated C₁ -C₆ alkyl groups, and C₁ -C₆ alkyl groups;and R³ and R⁴ together represent a group of formula (IV):

    --(CR.sup.a R.sup.b).sub.m --C(═Y)--                   (IV)

wherein each of R^(a) and R^(b) represents hydrogen or a C₁ -C₃ alkylgroup, m represents 1, or 2, and Y represents two hydrogen atoms or anoxygen atom.
 13. The compounds and salts of claim 11, wherein ring A isselected from the group consisting of unsubstituted aryl rings and arylrings substituted with at least one substituent selected from the groupconsisting of halogen atoms and C₁ -C₃ alkyl groups.
 14. The compoundsand salts of claim 11, wherein R³ and R⁴ together represent a group offormula (IV):

    --(CR.sup.a R.sup.b).sub.m --C(═Y)--                   (IV)

wherein each of R^(a) and R^(b) represents a hydrogen atom, and mrepresents 1, or 2, and Y represents two hydrogen atoms or an oxygenatom.
 15. A pharmaceutical composition comprising an effective analgesicamount of a compound of claim 11 or a pharmaceutically acceptable saltthereof together with a pharmaceutically acceptable carrier.
 16. Amethod for the relief of a pain, which comprises administering to ananimal in need thereof an effective analgesic amount of an analgesicdrug, wherein said analgesic drug comprises at least one compound ofclaim 11 or a pharmaceutically acceptable salt thereof.